Hematology

An antibiotic drug used to treat acne, among other things, may turn out to have potential well beyond that. Researchers from University of Antioquiain Medellin, Colombia, suggest that minocycline could be a promising antileukemic drug.

Minocycline is a well-established tetracycline derivative, used clinically since 1971, with a safe track record. But it also has nonantibiotic properties, exerting both antioxidant and antiapoptotic effects. There is even “compelling” preclinical evidence, the researchers say, that minocycline induces apoptosis in an acute myeloid leukemia cell line and a chronic myeloid leukemia cell line. Would the same be true of acute lymphoblastic leukemia (ALL) cells? To test their hypothesis, the researchers examined minocycline’s mechanism of action in the Jurkat cell line, an ALL tumor line established in the 1970s from the peripheral blood of a 14-year-old boy. 

The researchers found that minocycline did in fact induce apoptosis in Jurkat cells through a hydrogen peroxide (H₂O₂)-mediated signaling pathway. Indeed, they add, H₂O₂ triggers a whole cascade of adverse effects, including up-regulation of pro-apoptotic proteins. The researchers suggest that minocycline might even be capable of generating H₂O₂, which could explain the cytotoxic effects not only of minocycline, but of other tetracycline analogues. “Interestingly,” the researchers say, minocycline did all that without inducing oxidative stress or apoptosis makers in human peripheral blood lymphocyte cells.

The significance of their study is twofold, the researchers say: First, that minocycline is a safe and specific apoptosis-inducing drug against Jurkat cells in vitro; second, that it is pharmacologically well characterized and widely available.

The researchers note that no information is available on whether minocycline might efficiently kill ALL cells in vivo. However, they also note that minocycline has been found to be safe and well tolerated in doses up to 10 mg/kg in stroke patients—a dose that could be a sufficient concentration to reduce the viability of leukemia cell lines.

Source:
Ruiz-Moreno C, Velez-Pardo C, Jimenez-Del-Rio M. Toxicol In Vitro. 2018;50:336-346.
doi: 10.1016/j.tiv.2018.03.012

An antibiotic drug used to treat acne, among other things, may turn out to have potential well beyond that. Researchers from University of Antioquiain Medellin, Colombia, suggest that minocycline could be a promising antileukemic drug.

Minocycline is a well-established tetracycline derivative, used clinically since 1971, with a safe track record. But it also has nonantibiotic properties, exerting both antioxidant and antiapoptotic effects. There is even “compelling” preclinical evidence, the researchers say, that minocycline induces apoptosis in an acute myeloid leukemia cell line and a chronic myeloid leukemia cell line. Would the same be true of acute lymphoblastic leukemia (ALL) cells? To test their hypothesis, the researchers examined minocycline’s mechanism of action in the Jurkat cell line, an ALL tumor line established in the 1970s from the peripheral blood of a 14-year-old boy. 

The researchers found that minocycline did in fact induce apoptosis in Jurkat cells through a hydrogen peroxide (H₂O₂)-mediated signaling pathway. Indeed, they add, H₂O₂ triggers a whole cascade of adverse effects, including up-regulation of pro-apoptotic proteins. The researchers suggest that minocycline might even be capable of generating H₂O₂, which could explain the cytotoxic effects not only of minocycline, but of other tetracycline analogues. “Interestingly,” the researchers say, minocycline did all that without inducing oxidative stress or apoptosis makers in human peripheral blood lymphocyte cells.

The significance of their study is twofold, the researchers say: First, that minocycline is a safe and specific apoptosis-inducing drug against Jurkat cells in vitro; second, that it is pharmacologically well characterized and widely available.

The researchers note that no information is available on whether minocycline might efficiently kill ALL cells in vivo. However, they also note that minocycline has been found to be safe and well tolerated in doses up to 10 mg/kg in stroke patients—a dose that could be a sufficient concentration to reduce the viability of leukemia cell lines.

Source:
Ruiz-Moreno C, Velez-Pardo C, Jimenez-Del-Rio M. Toxicol In Vitro. 2018;50:336-346.
doi: 10.1016/j.tiv.2018.03.012

An antibiotic drug used to treat acne, among other things, may turn out to have potential well beyond that. Researchers from University of Antioquiain Medellin, Colombia, suggest that minocycline could be a promising antileukemic drug.

Minocycline is a well-established tetracycline derivative, used clinically since 1971, with a safe track record. But it also has nonantibiotic properties, exerting both antioxidant and antiapoptotic effects. There is even “compelling” preclinical evidence, the researchers say, that minocycline induces apoptosis in an acute myeloid leukemia cell line and a chronic myeloid leukemia cell line. Would the same be true of acute lymphoblastic leukemia (ALL) cells? To test their hypothesis, the researchers examined minocycline’s mechanism of action in the Jurkat cell line, an ALL tumor line established in the 1970s from the peripheral blood of a 14-year-old boy. 

The researchers found that minocycline did in fact induce apoptosis in Jurkat cells through a hydrogen peroxide (H₂O₂)-mediated signaling pathway. Indeed, they add, H₂O₂ triggers a whole cascade of adverse effects, including up-regulation of pro-apoptotic proteins. The researchers suggest that minocycline might even be capable of generating H₂O₂, which could explain the cytotoxic effects not only of minocycline, but of other tetracycline analogues. “Interestingly,” the researchers say, minocycline did all that without inducing oxidative stress or apoptosis makers in human peripheral blood lymphocyte cells.

The significance of their study is twofold, the researchers say: First, that minocycline is a safe and specific apoptosis-inducing drug against Jurkat cells in vitro; second, that it is pharmacologically well characterized and widely available.

The researchers note that no information is available on whether minocycline might efficiently kill ALL cells in vivo. However, they also note that minocycline has been found to be safe and well tolerated in doses up to 10 mg/kg in stroke patients—a dose that could be a sufficient concentration to reduce the viability of leukemia cell lines.

Source:
Ruiz-Moreno C, Velez-Pardo C, Jimenez-Del-Rio M. Toxicol In Vitro. 2018;50:336-346.
doi: 10.1016/j.tiv.2018.03.012

NEW ORLEANS – Both the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio proved to be better predictors of the presence or absence of deep vein thrombosis than the ubiquitous D-dimer test in a retrospective study, Jason Mouabbi, MD, reported at the annual meeting of the American College of Physicians.

What’s more, both the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) can be readily calculated from the readout of a complete blood count (CBC) with differential. A CBC costs an average of $16, and everybody that comes through a hospital emergency department gets one. In contrast, the average charge for a D-dimer test is about $231 nationwide, and depending upon the specific test used the results can take up to a couple of hours to come back, noted Dr. Mouabbi of St. John Hospital and Medical Center in Detroit.

“The NLR and PLR ratios offer a new, powerful, affordable, simple, and readily available tool in the hands of clinicians to help them in the diagnosis of DVT,” he said. “The NLR can be useful to rule out DVT when it’s negative, whereas PLR can be useful in ruling DVT when positive.”

Investigators in a variety of fields are looking at the NLR and PLR as emerging practical, easily obtainable biomarkers for systemic inflammation. And DVT is thought to be an inflammatory process, he explained.

Dr. Mouabbi presented a single-center retrospective study of 102 matched patients who presented with lower extremity swelling and had a CBC drawn, as well as a D-dimer test, on the same day they underwent a lower extremity Doppler ultrasound evaluation. In 51 patients, the ultrasound revealed the presence of DVT and anticoagulation was started. In the other 51 patients, the ultrasound exam was negative and they weren’t anticoagulated. Since the study purpose was to assess the implications of a primary elevation of NLR and/or PLR, patients with rheumatic diseases, inflammatory bowel disease, recent surgery, chronic renal or liver disease, inherited thrombophilia, infection, or other possible secondary causes of altered ratios were excluded from the study.

A positive NLR was considered 3.4 or higher, a positive PLR was a ratio of 230 or more, and a positive D-dimer level was 500 ng/mL or greater. The NLR and PLR collectively outperformed the D-dimer test in terms of sensitivity, specificity, positive predictive value, and negative predictive value.

In addition, 89% of the DVT group were classified as “double-positive,” meaning they were both NLR and PLR positive. That combination provided the best diagnostic value of all, since none of the controls were double-positive and only 2% were PLR positive.

While the results are encouraging, before NLR and PLR can supplant D-dimer in patients with suspected DVT in clinical practice a confirmatory prospective study should be carried out, according to Dr. Mouabbi. Ideally it should include the use of the Wells score, which is part of most diagnostic algorithms as a preliminary means of categorizing DVT probability as low, moderate, or high. However, the popularity of the Wells score has fallen off in the face of reports that the results are subjective and variable. Indeed, the Wells score was included in the electronic medical record of so few participants in Dr. Mouabbi’s study that he couldn’t evaluate its utility.

He reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

NEW ORLEANS – Both the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio proved to be better predictors of the presence or absence of deep vein thrombosis than the ubiquitous D-dimer test in a retrospective study, Jason Mouabbi, MD, reported at the annual meeting of the American College of Physicians.

What’s more, both the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) can be readily calculated from the readout of a complete blood count (CBC) with differential. A CBC costs an average of $16, and everybody that comes through a hospital emergency department gets one. In contrast, the average charge for a D-dimer test is about $231 nationwide, and depending upon the specific test used the results can take up to a couple of hours to come back, noted Dr. Mouabbi of St. John Hospital and Medical Center in Detroit.

“The NLR and PLR ratios offer a new, powerful, affordable, simple, and readily available tool in the hands of clinicians to help them in the diagnosis of DVT,” he said. “The NLR can be useful to rule out DVT when it’s negative, whereas PLR can be useful in ruling DVT when positive.”

Investigators in a variety of fields are looking at the NLR and PLR as emerging practical, easily obtainable biomarkers for systemic inflammation. And DVT is thought to be an inflammatory process, he explained.

Dr. Mouabbi presented a single-center retrospective study of 102 matched patients who presented with lower extremity swelling and had a CBC drawn, as well as a D-dimer test, on the same day they underwent a lower extremity Doppler ultrasound evaluation. In 51 patients, the ultrasound revealed the presence of DVT and anticoagulation was started. In the other 51 patients, the ultrasound exam was negative and they weren’t anticoagulated. Since the study purpose was to assess the implications of a primary elevation of NLR and/or PLR, patients with rheumatic diseases, inflammatory bowel disease, recent surgery, chronic renal or liver disease, inherited thrombophilia, infection, or other possible secondary causes of altered ratios were excluded from the study.

A positive NLR was considered 3.4 or higher, a positive PLR was a ratio of 230 or more, and a positive D-dimer level was 500 ng/mL or greater. The NLR and PLR collectively outperformed the D-dimer test in terms of sensitivity, specificity, positive predictive value, and negative predictive value.

In addition, 89% of the DVT group were classified as “double-positive,” meaning they were both NLR and PLR positive. That combination provided the best diagnostic value of all, since none of the controls were double-positive and only 2% were PLR positive.

While the results are encouraging, before NLR and PLR can supplant D-dimer in patients with suspected DVT in clinical practice a confirmatory prospective study should be carried out, according to Dr. Mouabbi. Ideally it should include the use of the Wells score, which is part of most diagnostic algorithms as a preliminary means of categorizing DVT probability as low, moderate, or high. However, the popularity of the Wells score has fallen off in the face of reports that the results are subjective and variable. Indeed, the Wells score was included in the electronic medical record of so few participants in Dr. Mouabbi’s study that he couldn’t evaluate its utility.

He reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

NEW ORLEANS – Both the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio proved to be better predictors of the presence or absence of deep vein thrombosis than the ubiquitous D-dimer test in a retrospective study, Jason Mouabbi, MD, reported at the annual meeting of the American College of Physicians.

What’s more, both the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) can be readily calculated from the readout of a complete blood count (CBC) with differential. A CBC costs an average of $16, and everybody that comes through a hospital emergency department gets one. In contrast, the average charge for a D-dimer test is about $231 nationwide, and depending upon the specific test used the results can take up to a couple of hours to come back, noted Dr. Mouabbi of St. John Hospital and Medical Center in Detroit.

“The NLR and PLR ratios offer a new, powerful, affordable, simple, and readily available tool in the hands of clinicians to help them in the diagnosis of DVT,” he said. “The NLR can be useful to rule out DVT when it’s negative, whereas PLR can be useful in ruling DVT when positive.”

Investigators in a variety of fields are looking at the NLR and PLR as emerging practical, easily obtainable biomarkers for systemic inflammation. And DVT is thought to be an inflammatory process, he explained.

Dr. Mouabbi presented a single-center retrospective study of 102 matched patients who presented with lower extremity swelling and had a CBC drawn, as well as a D-dimer test, on the same day they underwent a lower extremity Doppler ultrasound evaluation. In 51 patients, the ultrasound revealed the presence of DVT and anticoagulation was started. In the other 51 patients, the ultrasound exam was negative and they weren’t anticoagulated. Since the study purpose was to assess the implications of a primary elevation of NLR and/or PLR, patients with rheumatic diseases, inflammatory bowel disease, recent surgery, chronic renal or liver disease, inherited thrombophilia, infection, or other possible secondary causes of altered ratios were excluded from the study.

A positive NLR was considered 3.4 or higher, a positive PLR was a ratio of 230 or more, and a positive D-dimer level was 500 ng/mL or greater. The NLR and PLR collectively outperformed the D-dimer test in terms of sensitivity, specificity, positive predictive value, and negative predictive value.

In addition, 89% of the DVT group were classified as “double-positive,” meaning they were both NLR and PLR positive. That combination provided the best diagnostic value of all, since none of the controls were double-positive and only 2% were PLR positive.

While the results are encouraging, before NLR and PLR can supplant D-dimer in patients with suspected DVT in clinical practice a confirmatory prospective study should be carried out, according to Dr. Mouabbi. Ideally it should include the use of the Wells score, which is part of most diagnostic algorithms as a preliminary means of categorizing DVT probability as low, moderate, or high. However, the popularity of the Wells score has fallen off in the face of reports that the results are subjective and variable. Indeed, the Wells score was included in the electronic medical record of so few participants in Dr. Mouabbi’s study that he couldn’t evaluate its utility.

He reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

Medicare beneficiaries with myeloma who have prescription drug coverage have shown both decreased used of classic cytotoxic chemotherapy and better survival, according to new research.

vitanovski/Thinkstock.com

The findings suggested that prescription drug coverage brings better access to all existing treatment options.

“In this analysis of Medicare beneficiaries with myeloma, the receipt of therapy and survival differed according to prescription drug coverage status,” Adam Olszewski, MD, of the Lifespan Cancer Institute at Rhode Island Hospital in Providence, R.I., and his colleagues noted in the study. “Patients with PDP [prescription drug plan coverage through Medicare Part D] or OCC [other credible prescription drug coverage] more often received active myeloma care, compared to those without coverage,” they wrote in Journal of Clinical Oncology.

The researchers looked at 9,755 patients diagnosed with myeloma during 2006-2011 and examined what was used to treat the myeloma as a first line treatment. The cohort included 1,460 patients with no prescription drug coverage, 3,283 with PDP coverage, 3,607 with OCC, and 1,405 dual eligibility for Medicare and Medicaid coverage.

The study found that, compared with beneficiaries with no coverage, Medicare beneficiaries with PDP coverage “were 14% less likely to be treated with parenteral chemotherapy and 38% less likely to receive classic cytotoxic agents.” Additionally, among the cohort of beneficiaries that were without drug coverage prior to the diagnosis of myeloma, 41% actively obtained coverage, but even then, their survival was “significantly worse, compared with the beneficiaries who had coverage at diagnosis.”

Beneficiaries classified as having other credible coverage were 3% more likely to receive active myeloma care than were those without coverage, but the use of parenteral regimens did not differ between those groups.

Researchers noted that overall survival was 10% higher at 1 year and 6% higher at 3 years for beneficiaries with PDP coverage or OCC than it was for those without coverage, but they added that the analysis required cautious interpretation “as it is confounded by multiple baseline factors and mediated by the quality of cancer treatment. ... We could not discern whether worse survival in the group without coverage was a result of not receiving therapy at all, an inability to access IMiDs [immunomodulatory drugs], or poor control of other medical issues.”

However, a comparison with the control group “strongly suggest[s] that patients with myeloma without prescription drug coverage may not have received the most effective first-line therapy,” Dr. Olszewski and his colleagues added. “Survival for PDP and OCC groups remained identical, which supports the notion that having any prescription drug coverage contributed to optimal treatment and outcomes.”

The study was limited by the fact that unobserved clinical differences between beneficiaries with or without prescription drug coverage could have accounted for differences in mortality and that the comparison of treatments was restricted to parenteral regimens because IMiDs were observed to have been administered only for PDP enrollees.

Dr. Olszewski and study coauthor Amy Davidoff, PhD, of Yale University, New Haven, Conn., disclosed acting in consulting or advisory roles and receiving research funding from several pharmaceutical companies that develop cancer treatments.

[email protected]

SOURCE: Olszewski A et al. J Clin Oncol. 2018 Aug 16. doi: 10.1200/JCO.2018.77.8894.

Medicare beneficiaries with myeloma who have prescription drug coverage have shown both decreased used of classic cytotoxic chemotherapy and better survival, according to new research.

vitanovski/Thinkstock.com

The findings suggested that prescription drug coverage brings better access to all existing treatment options.

“In this analysis of Medicare beneficiaries with myeloma, the receipt of therapy and survival differed according to prescription drug coverage status,” Adam Olszewski, MD, of the Lifespan Cancer Institute at Rhode Island Hospital in Providence, R.I., and his colleagues noted in the study. “Patients with PDP [prescription drug plan coverage through Medicare Part D] or OCC [other credible prescription drug coverage] more often received active myeloma care, compared to those without coverage,” they wrote in Journal of Clinical Oncology.

The researchers looked at 9,755 patients diagnosed with myeloma during 2006-2011 and examined what was used to treat the myeloma as a first line treatment. The cohort included 1,460 patients with no prescription drug coverage, 3,283 with PDP coverage, 3,607 with OCC, and 1,405 dual eligibility for Medicare and Medicaid coverage.

The study found that, compared with beneficiaries with no coverage, Medicare beneficiaries with PDP coverage “were 14% less likely to be treated with parenteral chemotherapy and 38% less likely to receive classic cytotoxic agents.” Additionally, among the cohort of beneficiaries that were without drug coverage prior to the diagnosis of myeloma, 41% actively obtained coverage, but even then, their survival was “significantly worse, compared with the beneficiaries who had coverage at diagnosis.”

Beneficiaries classified as having other credible coverage were 3% more likely to receive active myeloma care than were those without coverage, but the use of parenteral regimens did not differ between those groups.

Researchers noted that overall survival was 10% higher at 1 year and 6% higher at 3 years for beneficiaries with PDP coverage or OCC than it was for those without coverage, but they added that the analysis required cautious interpretation “as it is confounded by multiple baseline factors and mediated by the quality of cancer treatment. ... We could not discern whether worse survival in the group without coverage was a result of not receiving therapy at all, an inability to access IMiDs [immunomodulatory drugs], or poor control of other medical issues.”

However, a comparison with the control group “strongly suggest[s] that patients with myeloma without prescription drug coverage may not have received the most effective first-line therapy,” Dr. Olszewski and his colleagues added. “Survival for PDP and OCC groups remained identical, which supports the notion that having any prescription drug coverage contributed to optimal treatment and outcomes.”

The study was limited by the fact that unobserved clinical differences between beneficiaries with or without prescription drug coverage could have accounted for differences in mortality and that the comparison of treatments was restricted to parenteral regimens because IMiDs were observed to have been administered only for PDP enrollees.

Dr. Olszewski and study coauthor Amy Davidoff, PhD, of Yale University, New Haven, Conn., disclosed acting in consulting or advisory roles and receiving research funding from several pharmaceutical companies that develop cancer treatments.

[email protected]

SOURCE: Olszewski A et al. J Clin Oncol. 2018 Aug 16. doi: 10.1200/JCO.2018.77.8894.

Medicare beneficiaries with myeloma who have prescription drug coverage have shown both decreased used of classic cytotoxic chemotherapy and better survival, according to new research.

vitanovski/Thinkstock.com

The findings suggested that prescription drug coverage brings better access to all existing treatment options.

“In this analysis of Medicare beneficiaries with myeloma, the receipt of therapy and survival differed according to prescription drug coverage status,” Adam Olszewski, MD, of the Lifespan Cancer Institute at Rhode Island Hospital in Providence, R.I., and his colleagues noted in the study. “Patients with PDP [prescription drug plan coverage through Medicare Part D] or OCC [other credible prescription drug coverage] more often received active myeloma care, compared to those without coverage,” they wrote in Journal of Clinical Oncology.

The researchers looked at 9,755 patients diagnosed with myeloma during 2006-2011 and examined what was used to treat the myeloma as a first line treatment. The cohort included 1,460 patients with no prescription drug coverage, 3,283 with PDP coverage, 3,607 with OCC, and 1,405 dual eligibility for Medicare and Medicaid coverage.

The study found that, compared with beneficiaries with no coverage, Medicare beneficiaries with PDP coverage “were 14% less likely to be treated with parenteral chemotherapy and 38% less likely to receive classic cytotoxic agents.” Additionally, among the cohort of beneficiaries that were without drug coverage prior to the diagnosis of myeloma, 41% actively obtained coverage, but even then, their survival was “significantly worse, compared with the beneficiaries who had coverage at diagnosis.”

Beneficiaries classified as having other credible coverage were 3% more likely to receive active myeloma care than were those without coverage, but the use of parenteral regimens did not differ between those groups.

Researchers noted that overall survival was 10% higher at 1 year and 6% higher at 3 years for beneficiaries with PDP coverage or OCC than it was for those without coverage, but they added that the analysis required cautious interpretation “as it is confounded by multiple baseline factors and mediated by the quality of cancer treatment. ... We could not discern whether worse survival in the group without coverage was a result of not receiving therapy at all, an inability to access IMiDs [immunomodulatory drugs], or poor control of other medical issues.”

However, a comparison with the control group “strongly suggest[s] that patients with myeloma without prescription drug coverage may not have received the most effective first-line therapy,” Dr. Olszewski and his colleagues added. “Survival for PDP and OCC groups remained identical, which supports the notion that having any prescription drug coverage contributed to optimal treatment and outcomes.”

The study was limited by the fact that unobserved clinical differences between beneficiaries with or without prescription drug coverage could have accounted for differences in mortality and that the comparison of treatments was restricted to parenteral regimens because IMiDs were observed to have been administered only for PDP enrollees.

Dr. Olszewski and study coauthor Amy Davidoff, PhD, of Yale University, New Haven, Conn., disclosed acting in consulting or advisory roles and receiving research funding from several pharmaceutical companies that develop cancer treatments.

[email protected]

SOURCE: Olszewski A et al. J Clin Oncol. 2018 Aug 16. doi: 10.1200/JCO.2018.77.8894.

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.

Exploiting T cells

The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.^1,2

Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.

Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.^1,3,4

Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.

Headlining advancements with CAR T cells

CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.^4,5

CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.⁶

It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.⁷

Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.⁸ Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.⁹

Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).¹⁰

Antibodies evolve

Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.

Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).¹¹ Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.¹²

Innovative design

Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.

The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.¹⁸

Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.¹⁹ Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.²⁰

21

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

New comprehensive guidelines for pediatric use of chimeric antigen receptor (CAR) T-cell therapies emphasize the need for a flexible approach to detect early signs of serious complications for younger patients treated with this emerging class of medicines.

Researchers at the University of Texas MD Anderson Cancer Center, Houston, and the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) developed the guidelines, which were published in Nature Reviews Clinical Oncology. The recommendations build on the guidelines for more general use of these medicines from MD Anderson’s CARTOX Program, which Nature Reviews Clinical Oncology published in 2017.

Among the chief concerns with this new class of medicines are cytokine-release syndrome (CRS) and CAR T cell-related encephalopathy syndrome (CRES), according to Kris Michael Mahadeo, MD MPH, of the MD Anderson Cancer Center and his coauthors of the new paper.

Some of the tools used for older patients in screening for complications with CAR T drugs don’t work as well with younger ones, Dr. Mahadeo said in an interview. For instance, at MD Anderson, a handwriting sample is used to monitor patients for CAR T cell-related encephalopathy syndrome, which has symptoms of confusion and delirium. Patients provide a baseline handwriting sample of a single sentence that’s scanned into the medical record, and then they are asked to write this again during their time in the hospital, he said. But this tool may not work for children too young to write well.

The new guidelines suggest using the Cornell Assessment of Pediatric Delirium (CAPD) or to evaluate a child’s mental state, asking questions about eye contact, and level of awareness and mood, Dr. Mahadeo said. An alternative for patients aged 12 years and older with greater cognitive ability is the CARTOX-10 grading system.

“The nurses who spent most of the day with these patients will observe them over their shift and kind of get an idea of what was normal and answer a series of questions” through the CAPD tool, which is already used in ICUs, Dr. Mahadeo said. “It takes into consideration both the nurses’ perception and the parents, or whoever is at the bedside with the child. So that if they have a concern, it gives them a point that actually escalates things upward.”

The newly published recommendations also remind physicians and others caring for young patients to pay attention to these reports.

“Parent and/or caregiver concerns should be addressed because early signs or symptoms of CRS can be subtle and best recognized by those who know the child best,” Dr. Mahadeo and his colleagues wrote in a summary of key recommendations in the paper.

The recommendations also noted a need for close monitoring for complications such as hypotension, hypocalcemia, and catheter-related pain in young patients who require a leukapheresis catheter for cell collection. Infant and younger children “might not verbalize these symptoms,” according to the researchers.

Other recommendations include:

• Obtaining the child’s assent when appropriate, with psychological services often aiding in this goal. Dr. Mahadeo and his colleagues recommend considering “age-appropriate advance directives.”
• Maintaining high vigilance for sinus tachycardia as an early sign of CRS, using age-specific normal range or baseline values.
• Giving pediatric dosing of tocilizumab, with patients weighing less than 30 kg receiving 12 mg/kg, and those weighing 30 kg or greater receiving 8 mg/kg.
• Considering participation with a prospective collaboration with intensive-care registries that could allow accurate data entry of cell-therapy variables into the Center for International Blood and Marrow Transplant Research registry by cell-therapy programs.

The Food and Drug Administration approved the first two CAR T-cell therapies in the United States in 2017: Novartis’ tisagenlecleucel (Kymriah) for children and young adults with B-cell precursor acute lymphoblastic leukemia and later for adults with large B-cell lymphoma; and axicabtagene ciloleucel (Yescarta), sold by Gilead, for adults with large B-cell lymphoma. The therapies involve reengineering a patient’s T cells such that they recognize the threat of cancer, and then introducing them back into the body. The European Medicines Agency’s Committee for Medicinal Products for Human Use in June recommended granting marketing authorization to these drugs.

In the new pediatric guidelines, Dr. Mahadeo and his colleagues noted the use of CAR T-cell therapies for treatment of solid tumors and other malignancies in children already “is being explored.” “Moreover, consideration of earlier or upfront use of CAR T-cell therapy might spare patients the acute and long-term toxicities associated with traditional chemotherapy and/or radiation regimens,” they wrote.

There’s been great interest in learning how to most safely use the CAR T cell therapies, said Helen Heslop, MD, of Baylor College of Medicine.

She pointed to a 2014 publication in the journal Blood from Daniel W. Lee and his colleagues as an earlier example of this research. By now, cancer centers will have worked out their own procedures for pediatric use of CAR T therapies, hewing to standards set by the Foundation for the Accreditation of Cellular Therapy (FACT), Dr. Heslop said.

Dr. Heslop also stressed the role of the FDA in requiring risk evaluation and management strategy programs for these drugs. All of this, including the new guidelines from Dr. Mahadeo and his colleagues, is part of a growing body of research into safe use of CAR T therapies, Dr. Heslop said.

“It’s an active area of research,” she said. “Most centers will look at all of it and then develop what works best in their own individual center for providing the best care for the patients.”

The newly published guidelines could prove an “important contribution” to managing the risk of CAR T therapies, Phyllis I. Warkentin, MD, chief medical officer for FACT, said in an interview, while stressing that they were not more or less important than other similar efforts. Physicians learning how to use the CAR T therapies may welcome new input, as most of what’s been published has been about adults, she said.

“You don’t have the luxury of a lot of time to be learning on the job, so to speak,” with CAR T therapies, she said. “Many of the toxicities are fairly severe and fairly sudden.”

Dr. Heslop has been on advisory board for Gilead and Novartis. Dr. Warkentin and Dr. Mahadeo each reported having no financial disclosures. Other authors of the guidelines paper reported a patent with applications in the field of gene-modified T cell therapy for cancer, as well as financial ties to Cellectis, NexImmune, Torque Pharma, Kite Pharma (a Gilead company), Poseida Therapeutics, Celgene, Novartis, and Unum Therapeutics.

SOURCE: Mahadeo KM et al. Nat Rev Clin Oncol. 2018 Aug 6. doi: 10.1038/s41571-018-0075-2.

New comprehensive guidelines for pediatric use of chimeric antigen receptor (CAR) T-cell therapies emphasize the need for a flexible approach to detect early signs of serious complications for younger patients treated with this emerging class of medicines.

Researchers at the University of Texas MD Anderson Cancer Center, Houston, and the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) developed the guidelines, which were published in Nature Reviews Clinical Oncology. The recommendations build on the guidelines for more general use of these medicines from MD Anderson’s CARTOX Program, which Nature Reviews Clinical Oncology published in 2017.

Among the chief concerns with this new class of medicines are cytokine-release syndrome (CRS) and CAR T cell-related encephalopathy syndrome (CRES), according to Kris Michael Mahadeo, MD MPH, of the MD Anderson Cancer Center and his coauthors of the new paper.

Some of the tools used for older patients in screening for complications with CAR T drugs don’t work as well with younger ones, Dr. Mahadeo said in an interview. For instance, at MD Anderson, a handwriting sample is used to monitor patients for CAR T cell-related encephalopathy syndrome, which has symptoms of confusion and delirium. Patients provide a baseline handwriting sample of a single sentence that’s scanned into the medical record, and then they are asked to write this again during their time in the hospital, he said. But this tool may not work for children too young to write well.

The new guidelines suggest using the Cornell Assessment of Pediatric Delirium (CAPD) or to evaluate a child’s mental state, asking questions about eye contact, and level of awareness and mood, Dr. Mahadeo said. An alternative for patients aged 12 years and older with greater cognitive ability is the CARTOX-10 grading system.

“The nurses who spent most of the day with these patients will observe them over their shift and kind of get an idea of what was normal and answer a series of questions” through the CAPD tool, which is already used in ICUs, Dr. Mahadeo said. “It takes into consideration both the nurses’ perception and the parents, or whoever is at the bedside with the child. So that if they have a concern, it gives them a point that actually escalates things upward.”

The newly published recommendations also remind physicians and others caring for young patients to pay attention to these reports.

“Parent and/or caregiver concerns should be addressed because early signs or symptoms of CRS can be subtle and best recognized by those who know the child best,” Dr. Mahadeo and his colleagues wrote in a summary of key recommendations in the paper.

The recommendations also noted a need for close monitoring for complications such as hypotension, hypocalcemia, and catheter-related pain in young patients who require a leukapheresis catheter for cell collection. Infant and younger children “might not verbalize these symptoms,” according to the researchers.

Other recommendations include:

• Obtaining the child’s assent when appropriate, with psychological services often aiding in this goal. Dr. Mahadeo and his colleagues recommend considering “age-appropriate advance directives.”
• Maintaining high vigilance for sinus tachycardia as an early sign of CRS, using age-specific normal range or baseline values.
• Giving pediatric dosing of tocilizumab, with patients weighing less than 30 kg receiving 12 mg/kg, and those weighing 30 kg or greater receiving 8 mg/kg.
• Considering participation with a prospective collaboration with intensive-care registries that could allow accurate data entry of cell-therapy variables into the Center for International Blood and Marrow Transplant Research registry by cell-therapy programs.

The Food and Drug Administration approved the first two CAR T-cell therapies in the United States in 2017: Novartis’ tisagenlecleucel (Kymriah) for children and young adults with B-cell precursor acute lymphoblastic leukemia and later for adults with large B-cell lymphoma; and axicabtagene ciloleucel (Yescarta), sold by Gilead, for adults with large B-cell lymphoma. The therapies involve reengineering a patient’s T cells such that they recognize the threat of cancer, and then introducing them back into the body. The European Medicines Agency’s Committee for Medicinal Products for Human Use in June recommended granting marketing authorization to these drugs.

In the new pediatric guidelines, Dr. Mahadeo and his colleagues noted the use of CAR T-cell therapies for treatment of solid tumors and other malignancies in children already “is being explored.” “Moreover, consideration of earlier or upfront use of CAR T-cell therapy might spare patients the acute and long-term toxicities associated with traditional chemotherapy and/or radiation regimens,” they wrote.

There’s been great interest in learning how to most safely use the CAR T cell therapies, said Helen Heslop, MD, of Baylor College of Medicine.

She pointed to a 2014 publication in the journal Blood from Daniel W. Lee and his colleagues as an earlier example of this research. By now, cancer centers will have worked out their own procedures for pediatric use of CAR T therapies, hewing to standards set by the Foundation for the Accreditation of Cellular Therapy (FACT), Dr. Heslop said.

Dr. Heslop also stressed the role of the FDA in requiring risk evaluation and management strategy programs for these drugs. All of this, including the new guidelines from Dr. Mahadeo and his colleagues, is part of a growing body of research into safe use of CAR T therapies, Dr. Heslop said.

“It’s an active area of research,” she said. “Most centers will look at all of it and then develop what works best in their own individual center for providing the best care for the patients.”

The newly published guidelines could prove an “important contribution” to managing the risk of CAR T therapies, Phyllis I. Warkentin, MD, chief medical officer for FACT, said in an interview, while stressing that they were not more or less important than other similar efforts. Physicians learning how to use the CAR T therapies may welcome new input, as most of what’s been published has been about adults, she said.

“You don’t have the luxury of a lot of time to be learning on the job, so to speak,” with CAR T therapies, she said. “Many of the toxicities are fairly severe and fairly sudden.”

Dr. Heslop has been on advisory board for Gilead and Novartis. Dr. Warkentin and Dr. Mahadeo each reported having no financial disclosures. Other authors of the guidelines paper reported a patent with applications in the field of gene-modified T cell therapy for cancer, as well as financial ties to Cellectis, NexImmune, Torque Pharma, Kite Pharma (a Gilead company), Poseida Therapeutics, Celgene, Novartis, and Unum Therapeutics.

SOURCE: Mahadeo KM et al. Nat Rev Clin Oncol. 2018 Aug 6. doi: 10.1038/s41571-018-0075-2.

New comprehensive guidelines for pediatric use of chimeric antigen receptor (CAR) T-cell therapies emphasize the need for a flexible approach to detect early signs of serious complications for younger patients treated with this emerging class of medicines.

Researchers at the University of Texas MD Anderson Cancer Center, Houston, and the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) developed the guidelines, which were published in Nature Reviews Clinical Oncology. The recommendations build on the guidelines for more general use of these medicines from MD Anderson’s CARTOX Program, which Nature Reviews Clinical Oncology published in 2017.

Among the chief concerns with this new class of medicines are cytokine-release syndrome (CRS) and CAR T cell-related encephalopathy syndrome (CRES), according to Kris Michael Mahadeo, MD MPH, of the MD Anderson Cancer Center and his coauthors of the new paper.

Some of the tools used for older patients in screening for complications with CAR T drugs don’t work as well with younger ones, Dr. Mahadeo said in an interview. For instance, at MD Anderson, a handwriting sample is used to monitor patients for CAR T cell-related encephalopathy syndrome, which has symptoms of confusion and delirium. Patients provide a baseline handwriting sample of a single sentence that’s scanned into the medical record, and then they are asked to write this again during their time in the hospital, he said. But this tool may not work for children too young to write well.

The new guidelines suggest using the Cornell Assessment of Pediatric Delirium (CAPD) or to evaluate a child’s mental state, asking questions about eye contact, and level of awareness and mood, Dr. Mahadeo said. An alternative for patients aged 12 years and older with greater cognitive ability is the CARTOX-10 grading system.

“The nurses who spent most of the day with these patients will observe them over their shift and kind of get an idea of what was normal and answer a series of questions” through the CAPD tool, which is already used in ICUs, Dr. Mahadeo said. “It takes into consideration both the nurses’ perception and the parents, or whoever is at the bedside with the child. So that if they have a concern, it gives them a point that actually escalates things upward.”

The newly published recommendations also remind physicians and others caring for young patients to pay attention to these reports.

“Parent and/or caregiver concerns should be addressed because early signs or symptoms of CRS can be subtle and best recognized by those who know the child best,” Dr. Mahadeo and his colleagues wrote in a summary of key recommendations in the paper.

The recommendations also noted a need for close monitoring for complications such as hypotension, hypocalcemia, and catheter-related pain in young patients who require a leukapheresis catheter for cell collection. Infant and younger children “might not verbalize these symptoms,” according to the researchers.

Other recommendations include:

• Obtaining the child’s assent when appropriate, with psychological services often aiding in this goal. Dr. Mahadeo and his colleagues recommend considering “age-appropriate advance directives.”
• Maintaining high vigilance for sinus tachycardia as an early sign of CRS, using age-specific normal range or baseline values.
• Giving pediatric dosing of tocilizumab, with patients weighing less than 30 kg receiving 12 mg/kg, and those weighing 30 kg or greater receiving 8 mg/kg.
• Considering participation with a prospective collaboration with intensive-care registries that could allow accurate data entry of cell-therapy variables into the Center for International Blood and Marrow Transplant Research registry by cell-therapy programs.

The Food and Drug Administration approved the first two CAR T-cell therapies in the United States in 2017: Novartis’ tisagenlecleucel (Kymriah) for children and young adults with B-cell precursor acute lymphoblastic leukemia and later for adults with large B-cell lymphoma; and axicabtagene ciloleucel (Yescarta), sold by Gilead, for adults with large B-cell lymphoma. The therapies involve reengineering a patient’s T cells such that they recognize the threat of cancer, and then introducing them back into the body. The European Medicines Agency’s Committee for Medicinal Products for Human Use in June recommended granting marketing authorization to these drugs.

In the new pediatric guidelines, Dr. Mahadeo and his colleagues noted the use of CAR T-cell therapies for treatment of solid tumors and other malignancies in children already “is being explored.” “Moreover, consideration of earlier or upfront use of CAR T-cell therapy might spare patients the acute and long-term toxicities associated with traditional chemotherapy and/or radiation regimens,” they wrote.

There’s been great interest in learning how to most safely use the CAR T cell therapies, said Helen Heslop, MD, of Baylor College of Medicine.

She pointed to a 2014 publication in the journal Blood from Daniel W. Lee and his colleagues as an earlier example of this research. By now, cancer centers will have worked out their own procedures for pediatric use of CAR T therapies, hewing to standards set by the Foundation for the Accreditation of Cellular Therapy (FACT), Dr. Heslop said.

Dr. Heslop also stressed the role of the FDA in requiring risk evaluation and management strategy programs for these drugs. All of this, including the new guidelines from Dr. Mahadeo and his colleagues, is part of a growing body of research into safe use of CAR T therapies, Dr. Heslop said.

“It’s an active area of research,” she said. “Most centers will look at all of it and then develop what works best in their own individual center for providing the best care for the patients.”

The newly published guidelines could prove an “important contribution” to managing the risk of CAR T therapies, Phyllis I. Warkentin, MD, chief medical officer for FACT, said in an interview, while stressing that they were not more or less important than other similar efforts. Physicians learning how to use the CAR T therapies may welcome new input, as most of what’s been published has been about adults, she said.

“You don’t have the luxury of a lot of time to be learning on the job, so to speak,” with CAR T therapies, she said. “Many of the toxicities are fairly severe and fairly sudden.”

Dr. Heslop has been on advisory board for Gilead and Novartis. Dr. Warkentin and Dr. Mahadeo each reported having no financial disclosures. Other authors of the guidelines paper reported a patent with applications in the field of gene-modified T cell therapy for cancer, as well as financial ties to Cellectis, NexImmune, Torque Pharma, Kite Pharma (a Gilead company), Poseida Therapeutics, Celgene, Novartis, and Unum Therapeutics.

SOURCE: Mahadeo KM et al. Nat Rev Clin Oncol. 2018 Aug 6. doi: 10.1038/s41571-018-0075-2.

The promise of broad-based genomic sequencing of advanced non–small cell lung cancer (NSCLC) to improve outcomes has not been realized in community oncology, results of a retrospective cohort study reported in JAMA suggest.

Investigators led by Carolyn J. Presley, MD, a thoracic and geriatric medical oncologist at the Ohio State University Comprehensive Cancer Center, Columbus, assessed outcomes among more than 5,500 patients with advanced nonsquamous NSCLC treated mainly in U.S. community practices. Overall, 15% had broad-based genomic testing (next-generation sequencing evaluating more than 30 cancer genes).

Main results showed that, among the patients having broad testing, less than 5% received a targeted treatment based on results that were not attainable with routine testing for common alterations in EGFR and ALK genes. Moreover, survival after broad testing was not better than that after routine testing.

“This study highlights how broad-based genomic sequencing has disseminated beyond traditional research settings ahead of a demonstrated association with better survival,” Dr. Presley and her coinvestigators write. They speculate that community uptake is being driven by the ease and cost of ordering a single comprehensive test, perceived benefit, attempts to conserve tissue, and hopes of improved survival if a targeted treatment is available.

“The lack of an association between broad-based genomic sequencing and survival is likely multifactorial,” the investigators maintain. “First, there were few genetic alterations identified with available targeted treatments. Second, even among those patients for whom targeted treatments were available, the treatments may not yield a substantial survival benefit or patients may not have had access to targeted agents due to financial barriers. Decision support for clinicians once they receive broad-based genomic sequencing results may also be needed.”
 

Study details

Dr. Presley and colleagues used the Flatiron Health Database to identify patients with advanced NSCLC who received care at 191 oncology practices across the United States during 2011-2016. The 5,688 patients studied had stage IIIB, stage IV, or unresectable nonsquamous NSCLC and received at least one line of treatment.

Overall, 15.4% received broad-based genomic sequencing of their tumor, while the rest received routine testing for EGFR and/or ALK alterations only, according to the results reported.

In the broadly tested group, merely 4.5% were given targeted treatment based on testing results. Another 9.8% received routine EGFR/ALK-targeted treatment, and 85.1% did not receive any targeted treatment.

The 12-month unadjusted mortality rate was 49.2% for patients undergoing broad testing, compared with 35.9% for patients undergoing routine testing.

In an instrumental variable analysis done to account for confounding, the 12-month predicted probability of death was 41.1% after broad testing and 44.4% after routine testing (P = .63).

Findings were similar in a propensity score–matched survival analysis (42.0% vs. 45.1%; hazard ratio, 0.92; P = .40), although there was some suggestion of a benefit of broad testing over routine testing in a Kaplan-Meier analysis among the entire unmatched cohort (HR, 0.69; P less than .001).

“Improved access to research clinical trials in the community setting may improve use of mutational data,” the investigators speculate. “Given the paucity of targeted agents, efforts to increase access to broad-based genomic sequencing should be paired with efforts to facilitate clinical trial enrollment.”

Dr. Presley disclosed that she receives grants from the Yale Lung SPORE Career Development Award, the Robert Wood Johnson/Veterans Affairs Clinical Scholars Program, and The Ohio State University K12 Training Grant for clinical faculty investigators. The study was funded by the Veterans Affairs Robert Wood Johnson Clinical Scholar Program and the Yale Lung SPORE Career Development Award.

SOURCE: Presley CJ et al. JAMA. 2018 Aug 7. doi: 10.1001/jama.2018.9824.

The promise of broad-based genomic sequencing of advanced non–small cell lung cancer (NSCLC) to improve outcomes has not been realized in community oncology, results of a retrospective cohort study reported in JAMA suggest.

Investigators led by Carolyn J. Presley, MD, a thoracic and geriatric medical oncologist at the Ohio State University Comprehensive Cancer Center, Columbus, assessed outcomes among more than 5,500 patients with advanced nonsquamous NSCLC treated mainly in U.S. community practices. Overall, 15% had broad-based genomic testing (next-generation sequencing evaluating more than 30 cancer genes).

Main results showed that, among the patients having broad testing, less than 5% received a targeted treatment based on results that were not attainable with routine testing for common alterations in EGFR and ALK genes. Moreover, survival after broad testing was not better than that after routine testing.

“This study highlights how broad-based genomic sequencing has disseminated beyond traditional research settings ahead of a demonstrated association with better survival,” Dr. Presley and her coinvestigators write. They speculate that community uptake is being driven by the ease and cost of ordering a single comprehensive test, perceived benefit, attempts to conserve tissue, and hopes of improved survival if a targeted treatment is available.

“The lack of an association between broad-based genomic sequencing and survival is likely multifactorial,” the investigators maintain. “First, there were few genetic alterations identified with available targeted treatments. Second, even among those patients for whom targeted treatments were available, the treatments may not yield a substantial survival benefit or patients may not have had access to targeted agents due to financial barriers. Decision support for clinicians once they receive broad-based genomic sequencing results may also be needed.”
 

Study details

Dr. Presley and colleagues used the Flatiron Health Database to identify patients with advanced NSCLC who received care at 191 oncology practices across the United States during 2011-2016. The 5,688 patients studied had stage IIIB, stage IV, or unresectable nonsquamous NSCLC and received at least one line of treatment.

Overall, 15.4% received broad-based genomic sequencing of their tumor, while the rest received routine testing for EGFR and/or ALK alterations only, according to the results reported.

In the broadly tested group, merely 4.5% were given targeted treatment based on testing results. Another 9.8% received routine EGFR/ALK-targeted treatment, and 85.1% did not receive any targeted treatment.

The 12-month unadjusted mortality rate was 49.2% for patients undergoing broad testing, compared with 35.9% for patients undergoing routine testing.

In an instrumental variable analysis done to account for confounding, the 12-month predicted probability of death was 41.1% after broad testing and 44.4% after routine testing (P = .63).

Findings were similar in a propensity score–matched survival analysis (42.0% vs. 45.1%; hazard ratio, 0.92; P = .40), although there was some suggestion of a benefit of broad testing over routine testing in a Kaplan-Meier analysis among the entire unmatched cohort (HR, 0.69; P less than .001).

“Improved access to research clinical trials in the community setting may improve use of mutational data,” the investigators speculate. “Given the paucity of targeted agents, efforts to increase access to broad-based genomic sequencing should be paired with efforts to facilitate clinical trial enrollment.”

Dr. Presley disclosed that she receives grants from the Yale Lung SPORE Career Development Award, the Robert Wood Johnson/Veterans Affairs Clinical Scholars Program, and The Ohio State University K12 Training Grant for clinical faculty investigators. The study was funded by the Veterans Affairs Robert Wood Johnson Clinical Scholar Program and the Yale Lung SPORE Career Development Award.

SOURCE: Presley CJ et al. JAMA. 2018 Aug 7. doi: 10.1001/jama.2018.9824.

The promise of broad-based genomic sequencing of advanced non–small cell lung cancer (NSCLC) to improve outcomes has not been realized in community oncology, results of a retrospective cohort study reported in JAMA suggest.

Investigators led by Carolyn J. Presley, MD, a thoracic and geriatric medical oncologist at the Ohio State University Comprehensive Cancer Center, Columbus, assessed outcomes among more than 5,500 patients with advanced nonsquamous NSCLC treated mainly in U.S. community practices. Overall, 15% had broad-based genomic testing (next-generation sequencing evaluating more than 30 cancer genes).

Main results showed that, among the patients having broad testing, less than 5% received a targeted treatment based on results that were not attainable with routine testing for common alterations in EGFR and ALK genes. Moreover, survival after broad testing was not better than that after routine testing.

“This study highlights how broad-based genomic sequencing has disseminated beyond traditional research settings ahead of a demonstrated association with better survival,” Dr. Presley and her coinvestigators write. They speculate that community uptake is being driven by the ease and cost of ordering a single comprehensive test, perceived benefit, attempts to conserve tissue, and hopes of improved survival if a targeted treatment is available.

“The lack of an association between broad-based genomic sequencing and survival is likely multifactorial,” the investigators maintain. “First, there were few genetic alterations identified with available targeted treatments. Second, even among those patients for whom targeted treatments were available, the treatments may not yield a substantial survival benefit or patients may not have had access to targeted agents due to financial barriers. Decision support for clinicians once they receive broad-based genomic sequencing results may also be needed.”
 

Study details

Dr. Presley and colleagues used the Flatiron Health Database to identify patients with advanced NSCLC who received care at 191 oncology practices across the United States during 2011-2016. The 5,688 patients studied had stage IIIB, stage IV, or unresectable nonsquamous NSCLC and received at least one line of treatment.

Overall, 15.4% received broad-based genomic sequencing of their tumor, while the rest received routine testing for EGFR and/or ALK alterations only, according to the results reported.

In the broadly tested group, merely 4.5% were given targeted treatment based on testing results. Another 9.8% received routine EGFR/ALK-targeted treatment, and 85.1% did not receive any targeted treatment.

The 12-month unadjusted mortality rate was 49.2% for patients undergoing broad testing, compared with 35.9% for patients undergoing routine testing.

In an instrumental variable analysis done to account for confounding, the 12-month predicted probability of death was 41.1% after broad testing and 44.4% after routine testing (P = .63).

Findings were similar in a propensity score–matched survival analysis (42.0% vs. 45.1%; hazard ratio, 0.92; P = .40), although there was some suggestion of a benefit of broad testing over routine testing in a Kaplan-Meier analysis among the entire unmatched cohort (HR, 0.69; P less than .001).

“Improved access to research clinical trials in the community setting may improve use of mutational data,” the investigators speculate. “Given the paucity of targeted agents, efforts to increase access to broad-based genomic sequencing should be paired with efforts to facilitate clinical trial enrollment.”

Dr. Presley disclosed that she receives grants from the Yale Lung SPORE Career Development Award, the Robert Wood Johnson/Veterans Affairs Clinical Scholars Program, and The Ohio State University K12 Training Grant for clinical faculty investigators. The study was funded by the Veterans Affairs Robert Wood Johnson Clinical Scholar Program and the Yale Lung SPORE Career Development Award.

SOURCE: Presley CJ et al. JAMA. 2018 Aug 7. doi: 10.1001/jama.2018.9824.

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for patients with chronic lymphocytic leukemia who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on chronic lymphocytic leukemia (CLL) to include “significant” developments in treatment. They were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the department of oncology at the University of Oxford (England), and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who could not take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients could also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended. TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib with rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote. However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplantation should be considered as a treatment option for patients who have either failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have a Richter transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5%-10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum is a registered charity that receives funding from a number of pharmaceutical companies.

SOURCE: Schuh AH et al. Br J Haematol. 2018 Jul 15. doi: 10.1111/bjh.15460.

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for patients with chronic lymphocytic leukemia who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on chronic lymphocytic leukemia (CLL) to include “significant” developments in treatment. They were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the department of oncology at the University of Oxford (England), and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who could not take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients could also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended. TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib with rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote. However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplantation should be considered as a treatment option for patients who have either failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have a Richter transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5%-10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum is a registered charity that receives funding from a number of pharmaceutical companies.

SOURCE: Schuh AH et al. Br J Haematol. 2018 Jul 15. doi: 10.1111/bjh.15460.

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for patients with chronic lymphocytic leukemia who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on chronic lymphocytic leukemia (CLL) to include “significant” developments in treatment. They were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the department of oncology at the University of Oxford (England), and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who could not take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients could also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended. TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib with rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote. However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplantation should be considered as a treatment option for patients who have either failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have a Richter transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5%-10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum is a registered charity that receives funding from a number of pharmaceutical companies.

SOURCE: Schuh AH et al. Br J Haematol. 2018 Jul 15. doi: 10.1111/bjh.15460.

Having health insurance can mean the difference between life and death for patients with follicular lymphoma, suggest results of a study showing that patients with private health insurance had nearly twofold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

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A review of records on more than 43,000 patients with follicular lymphoma (FL) in a national cancer registry showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket with either no insurance, Medicaid, or Medicare were, respectively, 1.96, 1.83, and 1.96 (P less than .0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL. Future studies on outcomes in FL should include insurance status as an important predictor,” Christopher R. Flowers, MD, of Emory University in Atlanta and his colleagues wrote in Blood.

“Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability,” they added.

The investigators noted that earlier research found that patients with Medicaid or no insurance were more likely than privately-insured patients to be diagnosed with cancers at advanced stages, and that some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, they extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

They identified a total of 43,648 patients aged 18 years or older who were diagnosed with FL from 2004 through 2014. They looked at both patients 18-64 years and those 65 years and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than age 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients aged 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P less than .0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and that patients with a score of 2 or greater had a HR of 3.1 (P less than .0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality health care may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr. Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

SOURCE: Goldstein JS et al. Blood. 2018 Jul 24. doi: 10.1182/blood-2018-03-839035.

Having health insurance can mean the difference between life and death for patients with follicular lymphoma, suggest results of a study showing that patients with private health insurance had nearly twofold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

Thinkstock

A review of records on more than 43,000 patients with follicular lymphoma (FL) in a national cancer registry showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket with either no insurance, Medicaid, or Medicare were, respectively, 1.96, 1.83, and 1.96 (P less than .0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL. Future studies on outcomes in FL should include insurance status as an important predictor,” Christopher R. Flowers, MD, of Emory University in Atlanta and his colleagues wrote in Blood.

“Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability,” they added.

The investigators noted that earlier research found that patients with Medicaid or no insurance were more likely than privately-insured patients to be diagnosed with cancers at advanced stages, and that some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, they extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

They identified a total of 43,648 patients aged 18 years or older who were diagnosed with FL from 2004 through 2014. They looked at both patients 18-64 years and those 65 years and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than age 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients aged 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P less than .0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and that patients with a score of 2 or greater had a HR of 3.1 (P less than .0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality health care may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr. Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

SOURCE: Goldstein JS et al. Blood. 2018 Jul 24. doi: 10.1182/blood-2018-03-839035.

Having health insurance can mean the difference between life and death for patients with follicular lymphoma, suggest results of a study showing that patients with private health insurance had nearly twofold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

Thinkstock

A review of records on more than 43,000 patients with follicular lymphoma (FL) in a national cancer registry showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket with either no insurance, Medicaid, or Medicare were, respectively, 1.96, 1.83, and 1.96 (P less than .0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL. Future studies on outcomes in FL should include insurance status as an important predictor,” Christopher R. Flowers, MD, of Emory University in Atlanta and his colleagues wrote in Blood.

“Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability,” they added.

The investigators noted that earlier research found that patients with Medicaid or no insurance were more likely than privately-insured patients to be diagnosed with cancers at advanced stages, and that some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, they extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

They identified a total of 43,648 patients aged 18 years or older who were diagnosed with FL from 2004 through 2014. They looked at both patients 18-64 years and those 65 years and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than age 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients aged 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P less than .0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and that patients with a score of 2 or greater had a HR of 3.1 (P less than .0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality health care may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr. Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

SOURCE: Goldstein JS et al. Blood. 2018 Jul 24. doi: 10.1182/blood-2018-03-839035.