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Are Food Emulsifiers Associated With Increased Cancer Risk?
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Food emulsifiers are among the most widespread food additives.
Ultraprocessed foods constitute a significant part of our diet, representing approximately 30% of energy intake in France.
Large epidemiologic studies have already linked diets rich in ultraprocessed products to an increased risk for cardiovascular diseases, diabetes, obesity, and mortality. Possible explanations for this association include the presence of additives, particularly emulsifiers. These additives are intended to improve the texture and shelf life of foods.
Recent experimental studies have shown that emulsifiers alter the gut microbiota and may lead to low-grade inflammation. Dysbiosis and chronic inflammation not only increase the risk for inflammatory bowel diseases but are also implicated in the etiology of several other chronic pathologies and certain extraintestinal cancers.
The NutriNet-Santé study provided extensive information on the dietary habits of > 100,000 French participants. A new analysis was conducted, examining the possible link between the presence of emulsifiers in the diet and cancer occurrence. Data from 92,000 participants (78.8% women) were utilized. They covered an average follow-up of 6.7 years, during which 2604 cancer cases were diagnosed, including 750 breast cancers, 322 prostate cancers, and 207 colorectal cancers.
In this cohort, the risk for cancer increased with a higher presence in the diet of products containing certain emulsifiers widely used in industrial food in Europe: Carrageenans (E407), mono- and diglycerides of fatty acids (E471), pectins (E440), and sodium carbonate (E500).
Notably, the highest consumption of mono- and diglycerides of fatty acids (E471) was associated with a 15% increase in the risk for all types of cancer, a 24% increase in breast cancer risk, and a 46% increase in prostate cancer risk. The highest consumption of carrageenans (E407) was associated with a 28% increase in breast cancer risk.
In an analysis by menopausal status, the risk for breast cancer before menopause was associated with high consumption of diphosphates (E450; 45% increase), pectins (E440; 55% increase), and sodium bicarbonate (E500; 48% increase). No link was found between emulsifier consumption and colorectal cancer risk. While some associations were observed for other emulsifiers, they did not persist in sensitivity analyses.
The European Food Safety Agency recently evaluated the risks of emulsifiers, however, and found no safety issues or need to limit daily consumption of several of them, notably E471.
It is certain that cancer is multifactorial, and a single factor (here, exposure to emulsifiers) will not significantly increase the risk. However, while not essential to human health, emulsifiers are widely prevalent in the global market. Therefore, if causality is established, the increased risk could translate into a significant number of preventable cancers at the population level. Confirmation of this causal link will need to be obtained through experimental and epidemiological studies.
This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Democratic Lawmakers Press Pfizer on Chemotherapy Drug Shortages
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
Unleashing Our Immune Response to Quash Cancer
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
Top US Oncology Regulator Seeks Changes in Drug Studies
Richard Pazdur, MD, who leads the cancer division at the US Food and Drug Administration (FDA), said there’s a need to simplify the paperwork involved in clinical trials. Before joining the FDA in 1999, Dr. Pazdur participated in and published cancer research. He says the informed consent forms used for studies have grown too elaborate over the years, such that they can intimidate even experts.
“When I read informed consents now in clinical trials, folks, it gives me a headache. Okay, I can’t follow them,” Dr. Pazdur said.
Dr. Pazdur said informed consent forms can be “mind-boggling” these days.
“They’re so damn complicated with so many damn questions being answered,” he said. “So our point is what’s the essential question that you need answered and what’s the quickest way of answering that question with the least amount of data that can be collected?”
Dr. Pazdur made these comments during a joint meeting of the FDA and the European Medicines Agency (EMA).
The meeting was a broad discussion about how to build on the successes seen in treatment of blood cancers in the past two decades. No formal recommendations were introduced or considered at the meeting. Instead, the meeting served as a chance for oncologists and patients to discuss ways to more quickly and efficiently address the key questions in drug research: Do medicines deliver a significant benefit to patients?
Dr. Pazdur also said at the meeting that there needs to be a way to attract more people to enroll in clinical trials.
“When I started in oncology, it was about 5%. When I’m sitting here now, 40 years later, it’s 5%. Basically it hasn’t moved,” he said at the discussion, held on February 1.
Ellin Berman, MD, of Memorial Sloan Kettering Cancer Center in New York, spoke at the meeting about the changes she has witnessed in her career in oncology. Until 2001, there were limited drug options, and physicians tried to get patients to transplant teams as possible. Then the FDA in 2001 approved imatinib to treat patients with chronic myelogenous leukemia (CML) that has the Philadelphia chromosome. That set the stage, Dr. Berman said, for a sea change in treatment of CML.
“The fellows now have no idea what it is like to talk to a CML patient about transplant and the question is which among the treasures we have of drugs do we start people on? And that’s always a conversation,” Dr. Berman said.
She noted that advances in treatment have also let some female patients get pregnant and have children.
“We have at least half a dozen women who bring their kids to clinic. And boy, if that doesn’t bring tears to our eyes, our collective eyes, I don’t know what does,” she said.
Dr. Pazdur also recalled his experience treating patients in the 1970s and 1980s for cancers for which “you had nothing so to speak” in terms of effective treatment.
“So then ask yourself the question, what would their stories be now?” with the many options available, Dr. Pazdur said.
Seeking clinician feedback
To try to improve the development and testing of cancer drugs, the FDA is seeking to get more feedback from clinicians about which questions trials should address, Dr. Pazdur said.
The agency is considering a way to poll clinicians on what their most crucial questions are about the medicines, he said. Better design of trial questions might serve to improve enrollment in studies.
“What we’re thinking of doing is taking the common disease areas and asking clinicians what are the five basic questions that you want answered in the next 5 years,” he said.
He cited PD-1 drugs as a possible example of a class where regulators could consider new approaches. There could be a discussion about the safety data collection for this class of drugs, which has been used by millions of patients.
Dr. Pazdur said he has been discussing these kinds of themes with his European and Japanese counterparts, who also are interested in simplifying clinical trials.
The goal is to have trials better represent real-world experiences rather than “artificial” ones created when patients must meet extensive eligibility requirements. Improved use of emerging technologies could aid in the needed streamlining, Dr. Pazdur said.
“As an oncology community, we have made our lives somewhat too complicated and need to draw back and ask the basic questions,” Dr. Pazdur said.
Richard Pazdur, MD, who leads the cancer division at the US Food and Drug Administration (FDA), said there’s a need to simplify the paperwork involved in clinical trials. Before joining the FDA in 1999, Dr. Pazdur participated in and published cancer research. He says the informed consent forms used for studies have grown too elaborate over the years, such that they can intimidate even experts.
“When I read informed consents now in clinical trials, folks, it gives me a headache. Okay, I can’t follow them,” Dr. Pazdur said.
Dr. Pazdur said informed consent forms can be “mind-boggling” these days.
“They’re so damn complicated with so many damn questions being answered,” he said. “So our point is what’s the essential question that you need answered and what’s the quickest way of answering that question with the least amount of data that can be collected?”
Dr. Pazdur made these comments during a joint meeting of the FDA and the European Medicines Agency (EMA).
The meeting was a broad discussion about how to build on the successes seen in treatment of blood cancers in the past two decades. No formal recommendations were introduced or considered at the meeting. Instead, the meeting served as a chance for oncologists and patients to discuss ways to more quickly and efficiently address the key questions in drug research: Do medicines deliver a significant benefit to patients?
Dr. Pazdur also said at the meeting that there needs to be a way to attract more people to enroll in clinical trials.
“When I started in oncology, it was about 5%. When I’m sitting here now, 40 years later, it’s 5%. Basically it hasn’t moved,” he said at the discussion, held on February 1.
Ellin Berman, MD, of Memorial Sloan Kettering Cancer Center in New York, spoke at the meeting about the changes she has witnessed in her career in oncology. Until 2001, there were limited drug options, and physicians tried to get patients to transplant teams as possible. Then the FDA in 2001 approved imatinib to treat patients with chronic myelogenous leukemia (CML) that has the Philadelphia chromosome. That set the stage, Dr. Berman said, for a sea change in treatment of CML.
“The fellows now have no idea what it is like to talk to a CML patient about transplant and the question is which among the treasures we have of drugs do we start people on? And that’s always a conversation,” Dr. Berman said.
She noted that advances in treatment have also let some female patients get pregnant and have children.
“We have at least half a dozen women who bring their kids to clinic. And boy, if that doesn’t bring tears to our eyes, our collective eyes, I don’t know what does,” she said.
Dr. Pazdur also recalled his experience treating patients in the 1970s and 1980s for cancers for which “you had nothing so to speak” in terms of effective treatment.
“So then ask yourself the question, what would their stories be now?” with the many options available, Dr. Pazdur said.
Seeking clinician feedback
To try to improve the development and testing of cancer drugs, the FDA is seeking to get more feedback from clinicians about which questions trials should address, Dr. Pazdur said.
The agency is considering a way to poll clinicians on what their most crucial questions are about the medicines, he said. Better design of trial questions might serve to improve enrollment in studies.
“What we’re thinking of doing is taking the common disease areas and asking clinicians what are the five basic questions that you want answered in the next 5 years,” he said.
He cited PD-1 drugs as a possible example of a class where regulators could consider new approaches. There could be a discussion about the safety data collection for this class of drugs, which has been used by millions of patients.
Dr. Pazdur said he has been discussing these kinds of themes with his European and Japanese counterparts, who also are interested in simplifying clinical trials.
The goal is to have trials better represent real-world experiences rather than “artificial” ones created when patients must meet extensive eligibility requirements. Improved use of emerging technologies could aid in the needed streamlining, Dr. Pazdur said.
“As an oncology community, we have made our lives somewhat too complicated and need to draw back and ask the basic questions,” Dr. Pazdur said.
Richard Pazdur, MD, who leads the cancer division at the US Food and Drug Administration (FDA), said there’s a need to simplify the paperwork involved in clinical trials. Before joining the FDA in 1999, Dr. Pazdur participated in and published cancer research. He says the informed consent forms used for studies have grown too elaborate over the years, such that they can intimidate even experts.
“When I read informed consents now in clinical trials, folks, it gives me a headache. Okay, I can’t follow them,” Dr. Pazdur said.
Dr. Pazdur said informed consent forms can be “mind-boggling” these days.
“They’re so damn complicated with so many damn questions being answered,” he said. “So our point is what’s the essential question that you need answered and what’s the quickest way of answering that question with the least amount of data that can be collected?”
Dr. Pazdur made these comments during a joint meeting of the FDA and the European Medicines Agency (EMA).
The meeting was a broad discussion about how to build on the successes seen in treatment of blood cancers in the past two decades. No formal recommendations were introduced or considered at the meeting. Instead, the meeting served as a chance for oncologists and patients to discuss ways to more quickly and efficiently address the key questions in drug research: Do medicines deliver a significant benefit to patients?
Dr. Pazdur also said at the meeting that there needs to be a way to attract more people to enroll in clinical trials.
“When I started in oncology, it was about 5%. When I’m sitting here now, 40 years later, it’s 5%. Basically it hasn’t moved,” he said at the discussion, held on February 1.
Ellin Berman, MD, of Memorial Sloan Kettering Cancer Center in New York, spoke at the meeting about the changes she has witnessed in her career in oncology. Until 2001, there were limited drug options, and physicians tried to get patients to transplant teams as possible. Then the FDA in 2001 approved imatinib to treat patients with chronic myelogenous leukemia (CML) that has the Philadelphia chromosome. That set the stage, Dr. Berman said, for a sea change in treatment of CML.
“The fellows now have no idea what it is like to talk to a CML patient about transplant and the question is which among the treasures we have of drugs do we start people on? And that’s always a conversation,” Dr. Berman said.
She noted that advances in treatment have also let some female patients get pregnant and have children.
“We have at least half a dozen women who bring their kids to clinic. And boy, if that doesn’t bring tears to our eyes, our collective eyes, I don’t know what does,” she said.
Dr. Pazdur also recalled his experience treating patients in the 1970s and 1980s for cancers for which “you had nothing so to speak” in terms of effective treatment.
“So then ask yourself the question, what would their stories be now?” with the many options available, Dr. Pazdur said.
Seeking clinician feedback
To try to improve the development and testing of cancer drugs, the FDA is seeking to get more feedback from clinicians about which questions trials should address, Dr. Pazdur said.
The agency is considering a way to poll clinicians on what their most crucial questions are about the medicines, he said. Better design of trial questions might serve to improve enrollment in studies.
“What we’re thinking of doing is taking the common disease areas and asking clinicians what are the five basic questions that you want answered in the next 5 years,” he said.
He cited PD-1 drugs as a possible example of a class where regulators could consider new approaches. There could be a discussion about the safety data collection for this class of drugs, which has been used by millions of patients.
Dr. Pazdur said he has been discussing these kinds of themes with his European and Japanese counterparts, who also are interested in simplifying clinical trials.
The goal is to have trials better represent real-world experiences rather than “artificial” ones created when patients must meet extensive eligibility requirements. Improved use of emerging technologies could aid in the needed streamlining, Dr. Pazdur said.
“As an oncology community, we have made our lives somewhat too complicated and need to draw back and ask the basic questions,” Dr. Pazdur said.
Hematology is in the Brodsky family’s blood
In interviews, Robert and Max Brodsky spoke about the appeal of hematology and the threads that unite them with family members who came before. The elder Brodsky also talked about the work that’s made him the proudest during his year-long presidency at ASH.
Robert A. Brodsky is professor of medicine and director of hematology at Johns Hopkins University, Baltimore. He is stepping down as ASH president at its annual meeting in San Diego, December 9-12. Here are excerpts from our conversation:
Q: What drew your dad into medicine?
Dr. Robert A. Brodsky: He was going through his medical training at the University of Pennsylvania, then the Vietnam War came, and he served at the National Institutes of Health in what they referred to as the Yellow Berets. He got very interested in retroviruses and viruses that lead to cancer, which was a foreign idea at the time. This led him into hematology, stem cells, and myeloproliferative disorders.
He had a very successful career in hematology and just loved it. He performed the first bone marrow transplant in the tristate area of Pennsylvania, Delaware, and New Jersey.
Q: What did he like about hematology specifically?
Dr. Robert A. Brodsky: It’s a fascinating field, probably the most scientific area of medicine. It’s so easy to access blood and bone marrow. You can grow it, you can look at it, you can see it. It’s hard to do that with a lung, heart, kidney, or brain. Even back then, they could translate some of the science. What really drew him to hematology — and me, for that matter — was looking at a blood smear or bone marrow and being able to make a diagnosis. The other thing is the personal aspect. Hematologists tend to like the long-term relationships that they develop with their patients over the years.
Q: What were the biggest transformations in hematology during his career?
Dr. Robert A. Brodsky: Bone marrow transplant had the biggest impact, and it’s an area he really pioneered. He was very much involved in some of the early bone marrow transplants and was very close with Dr. George W. Santos, who was at Johns Hopkins and one of the big pioneers in that area as well. To be able to take marrow from related donors, get it to grow without the patient rejecting it, and cure a disease, was really huge. When he started doing this, patients had no other option. To see patients be cured was incredibly satisfying to him.
Q: How did you end up following your father into hematology?
Dr. Robert A. Brodsky: My brother Jeff, who’s a surgeon and older than me, knew he was going into medicine — probably about 3 hours after he was born. I came to it late. I was a political science major as an undergrad and really trying to figure out what I wanted to do. In my sophomore year, I decided I wanted to give this a shot. My dad worked very hard, long hours, but you could tell he loved what he did. And he was never absent, always involved in our lives and still made time for everyone. At some level, that must have had an influence on me.
Q: What has changed in hematology over your 30-plus years in medicine?
A: When I look back at when I was a fellow, it’s just mind-boggling how many lethal or life-threatening diseases are now pretty easy to treat. I studied disorders like aplastic anemia, which was very fatal. Without treatment, patients would die within a year. Now, over 95% are cured. Another classic examples is chronic myeloid leukemia disorder. Back when I was a fellow, the median survival for CML was maybe 4 to 6 years. Now, Kareem Abdul Jabbar has had this[for about 15 years]. Also a lot of hematologic malignancies are being cured with immunotherapy approaches. We’ve figured out the pathophysiology of a lot of diseases, and there are incredible genetic diagnostic assays.
Q: What was your father’s relationship with ASH?
Dr. Robert A. Brodsky: The first ASH meeting was 1958 in Atlantic City, New Jersey. There were 300 hematologists there, and my dad was one of them. We’re going to have over 30,000 people in San Diego, which is a record, and another 5,000 or 6,000 virtually.
Q: As ASH president, what are your biggest accomplishments when it comes to addressing the shortage of hematologists and other issues?
Dr. Robert A. Brodsky: ASH is investing $19 million to develop fellowships with a focus on hematology.* This is going to put lots of new hematologists into the workforce over the next 5 to 10 years. We’ve also been working on the Maintenance of Certification [MOC] process to make it less onerous on physicians. It’s really a bad process, and it’s not just ASH [that’s complaining], it’s all of medicine. We’re hearing this from GI, endocrine, renal and the general internists.
[In a September 2023 letter to the American Board of Internal Medicine’s president and chief officer, Dr. Brodsky wrote that “ASH continues to support the importance of lifelong learning for hematologists via a program that is evidence-based, relevant to one’s practice, and transparent; however, these three basic requirements are not met by the current ABIM MOC program.” ASH is calling for a new and reformed MOC program.]
Q: What convinced ASH to expand its journals by adding Blood Neoplasia and Blood Vessels, Thrombosis & Hemostasis?
Dr. Robert A. Brodsky: ASH has two flagship journals right now, Blood and Blood Advances, and they’re both very competitive, high-impact journals. It turns out there’s not enough room to publish all the new science, and they end up rejecting the majority of the submissions that come to them. We decided to keep these journals in the ASH family because there’s some fantastic clinical trials and science that would be going elsewhere.
Dr. Brodsky’s sons both have medical degrees: Brett Brodsky, DO, is a resident at Virginia Commonwealth University who plans to become a sports medicine specialist, and Max Brodsky, MD, is a second-year fellow in hematology at Johns Hopkins University.
In an interview, Max Brodsky, MD, talked about the roots of his family’s dedication to caring for others.
Q: What drew you to hematology?
Dr. Max Brodsky: I’ve watched both my dad and my grandfather be leaders in the field as both physicians and scientists, and that was very inspirational for me to see. And I went to a medical school [Drexel University College of Medicine] that my dad went to and where my grandfather was on faculty. That was like walking in their footsteps in a major way.
Q: What do you hope to focus on as a hematologist?
Dr. Max Brodsky: I’m still working through that, but I am really interested in thrombotic thrombocytopenic purpura. Patients used to not be able to survive their initial episodes, but now we have good treatments and are able to follow them as outpatients. With this whole cohort of patients that are surviving, we’re seeing that they have more health problems — more heart disease, more strokes and kidney disease. There’s a whole growing field exploring how to treat these patients for their lifespan.
Q: How do you deal with the reality that more of your patients will die than in some other medical fields?
Dr. Max Brodsky: It is challenging, but I also see those moments as opportunities to support patients and families. I’m good at connecting to patients and families who are in scary situations. I’ve always had that skill of putting people at ease, making people feel calm, knowing that they can trust me, and I have their best interests in mind.
Q: Why do you think your family is so committed to medicine?
Dr. Max Brodsky: We’re Jewish, and looking to help the world is one of the main core values of Judaism. The Torah expects us to make this world better. Actually, my great-grandfather Max, whom I’m named after, used to dig tunnels to help people escape Ukraine and get to freedom. He was always looking to help others as well. My great-grandmother was shot crossing the border escaping from Ukraine, and he carried her the whole way to the boat. They lived in very poor West Philadelphia and poured everything into my grandfather. He became a great doctor, and his sons and his grandchildren are in medicine today.
*Correction, 12/11: A previous version of this story misstated the amount of ASH’s $19 million investment in developing fellowships with a focus on hematology.
In interviews, Robert and Max Brodsky spoke about the appeal of hematology and the threads that unite them with family members who came before. The elder Brodsky also talked about the work that’s made him the proudest during his year-long presidency at ASH.
Robert A. Brodsky is professor of medicine and director of hematology at Johns Hopkins University, Baltimore. He is stepping down as ASH president at its annual meeting in San Diego, December 9-12. Here are excerpts from our conversation:
Q: What drew your dad into medicine?
Dr. Robert A. Brodsky: He was going through his medical training at the University of Pennsylvania, then the Vietnam War came, and he served at the National Institutes of Health in what they referred to as the Yellow Berets. He got very interested in retroviruses and viruses that lead to cancer, which was a foreign idea at the time. This led him into hematology, stem cells, and myeloproliferative disorders.
He had a very successful career in hematology and just loved it. He performed the first bone marrow transplant in the tristate area of Pennsylvania, Delaware, and New Jersey.
Q: What did he like about hematology specifically?
Dr. Robert A. Brodsky: It’s a fascinating field, probably the most scientific area of medicine. It’s so easy to access blood and bone marrow. You can grow it, you can look at it, you can see it. It’s hard to do that with a lung, heart, kidney, or brain. Even back then, they could translate some of the science. What really drew him to hematology — and me, for that matter — was looking at a blood smear or bone marrow and being able to make a diagnosis. The other thing is the personal aspect. Hematologists tend to like the long-term relationships that they develop with their patients over the years.
Q: What were the biggest transformations in hematology during his career?
Dr. Robert A. Brodsky: Bone marrow transplant had the biggest impact, and it’s an area he really pioneered. He was very much involved in some of the early bone marrow transplants and was very close with Dr. George W. Santos, who was at Johns Hopkins and one of the big pioneers in that area as well. To be able to take marrow from related donors, get it to grow without the patient rejecting it, and cure a disease, was really huge. When he started doing this, patients had no other option. To see patients be cured was incredibly satisfying to him.
Q: How did you end up following your father into hematology?
Dr. Robert A. Brodsky: My brother Jeff, who’s a surgeon and older than me, knew he was going into medicine — probably about 3 hours after he was born. I came to it late. I was a political science major as an undergrad and really trying to figure out what I wanted to do. In my sophomore year, I decided I wanted to give this a shot. My dad worked very hard, long hours, but you could tell he loved what he did. And he was never absent, always involved in our lives and still made time for everyone. At some level, that must have had an influence on me.
Q: What has changed in hematology over your 30-plus years in medicine?
A: When I look back at when I was a fellow, it’s just mind-boggling how many lethal or life-threatening diseases are now pretty easy to treat. I studied disorders like aplastic anemia, which was very fatal. Without treatment, patients would die within a year. Now, over 95% are cured. Another classic examples is chronic myeloid leukemia disorder. Back when I was a fellow, the median survival for CML was maybe 4 to 6 years. Now, Kareem Abdul Jabbar has had this[for about 15 years]. Also a lot of hematologic malignancies are being cured with immunotherapy approaches. We’ve figured out the pathophysiology of a lot of diseases, and there are incredible genetic diagnostic assays.
Q: What was your father’s relationship with ASH?
Dr. Robert A. Brodsky: The first ASH meeting was 1958 in Atlantic City, New Jersey. There were 300 hematologists there, and my dad was one of them. We’re going to have over 30,000 people in San Diego, which is a record, and another 5,000 or 6,000 virtually.
Q: As ASH president, what are your biggest accomplishments when it comes to addressing the shortage of hematologists and other issues?
Dr. Robert A. Brodsky: ASH is investing $19 million to develop fellowships with a focus on hematology.* This is going to put lots of new hematologists into the workforce over the next 5 to 10 years. We’ve also been working on the Maintenance of Certification [MOC] process to make it less onerous on physicians. It’s really a bad process, and it’s not just ASH [that’s complaining], it’s all of medicine. We’re hearing this from GI, endocrine, renal and the general internists.
[In a September 2023 letter to the American Board of Internal Medicine’s president and chief officer, Dr. Brodsky wrote that “ASH continues to support the importance of lifelong learning for hematologists via a program that is evidence-based, relevant to one’s practice, and transparent; however, these three basic requirements are not met by the current ABIM MOC program.” ASH is calling for a new and reformed MOC program.]
Q: What convinced ASH to expand its journals by adding Blood Neoplasia and Blood Vessels, Thrombosis & Hemostasis?
Dr. Robert A. Brodsky: ASH has two flagship journals right now, Blood and Blood Advances, and they’re both very competitive, high-impact journals. It turns out there’s not enough room to publish all the new science, and they end up rejecting the majority of the submissions that come to them. We decided to keep these journals in the ASH family because there’s some fantastic clinical trials and science that would be going elsewhere.
Dr. Brodsky’s sons both have medical degrees: Brett Brodsky, DO, is a resident at Virginia Commonwealth University who plans to become a sports medicine specialist, and Max Brodsky, MD, is a second-year fellow in hematology at Johns Hopkins University.
In an interview, Max Brodsky, MD, talked about the roots of his family’s dedication to caring for others.
Q: What drew you to hematology?
Dr. Max Brodsky: I’ve watched both my dad and my grandfather be leaders in the field as both physicians and scientists, and that was very inspirational for me to see. And I went to a medical school [Drexel University College of Medicine] that my dad went to and where my grandfather was on faculty. That was like walking in their footsteps in a major way.
Q: What do you hope to focus on as a hematologist?
Dr. Max Brodsky: I’m still working through that, but I am really interested in thrombotic thrombocytopenic purpura. Patients used to not be able to survive their initial episodes, but now we have good treatments and are able to follow them as outpatients. With this whole cohort of patients that are surviving, we’re seeing that they have more health problems — more heart disease, more strokes and kidney disease. There’s a whole growing field exploring how to treat these patients for their lifespan.
Q: How do you deal with the reality that more of your patients will die than in some other medical fields?
Dr. Max Brodsky: It is challenging, but I also see those moments as opportunities to support patients and families. I’m good at connecting to patients and families who are in scary situations. I’ve always had that skill of putting people at ease, making people feel calm, knowing that they can trust me, and I have their best interests in mind.
Q: Why do you think your family is so committed to medicine?
Dr. Max Brodsky: We’re Jewish, and looking to help the world is one of the main core values of Judaism. The Torah expects us to make this world better. Actually, my great-grandfather Max, whom I’m named after, used to dig tunnels to help people escape Ukraine and get to freedom. He was always looking to help others as well. My great-grandmother was shot crossing the border escaping from Ukraine, and he carried her the whole way to the boat. They lived in very poor West Philadelphia and poured everything into my grandfather. He became a great doctor, and his sons and his grandchildren are in medicine today.
*Correction, 12/11: A previous version of this story misstated the amount of ASH’s $19 million investment in developing fellowships with a focus on hematology.
In interviews, Robert and Max Brodsky spoke about the appeal of hematology and the threads that unite them with family members who came before. The elder Brodsky also talked about the work that’s made him the proudest during his year-long presidency at ASH.
Robert A. Brodsky is professor of medicine and director of hematology at Johns Hopkins University, Baltimore. He is stepping down as ASH president at its annual meeting in San Diego, December 9-12. Here are excerpts from our conversation:
Q: What drew your dad into medicine?
Dr. Robert A. Brodsky: He was going through his medical training at the University of Pennsylvania, then the Vietnam War came, and he served at the National Institutes of Health in what they referred to as the Yellow Berets. He got very interested in retroviruses and viruses that lead to cancer, which was a foreign idea at the time. This led him into hematology, stem cells, and myeloproliferative disorders.
He had a very successful career in hematology and just loved it. He performed the first bone marrow transplant in the tristate area of Pennsylvania, Delaware, and New Jersey.
Q: What did he like about hematology specifically?
Dr. Robert A. Brodsky: It’s a fascinating field, probably the most scientific area of medicine. It’s so easy to access blood and bone marrow. You can grow it, you can look at it, you can see it. It’s hard to do that with a lung, heart, kidney, or brain. Even back then, they could translate some of the science. What really drew him to hematology — and me, for that matter — was looking at a blood smear or bone marrow and being able to make a diagnosis. The other thing is the personal aspect. Hematologists tend to like the long-term relationships that they develop with their patients over the years.
Q: What were the biggest transformations in hematology during his career?
Dr. Robert A. Brodsky: Bone marrow transplant had the biggest impact, and it’s an area he really pioneered. He was very much involved in some of the early bone marrow transplants and was very close with Dr. George W. Santos, who was at Johns Hopkins and one of the big pioneers in that area as well. To be able to take marrow from related donors, get it to grow without the patient rejecting it, and cure a disease, was really huge. When he started doing this, patients had no other option. To see patients be cured was incredibly satisfying to him.
Q: How did you end up following your father into hematology?
Dr. Robert A. Brodsky: My brother Jeff, who’s a surgeon and older than me, knew he was going into medicine — probably about 3 hours after he was born. I came to it late. I was a political science major as an undergrad and really trying to figure out what I wanted to do. In my sophomore year, I decided I wanted to give this a shot. My dad worked very hard, long hours, but you could tell he loved what he did. And he was never absent, always involved in our lives and still made time for everyone. At some level, that must have had an influence on me.
Q: What has changed in hematology over your 30-plus years in medicine?
A: When I look back at when I was a fellow, it’s just mind-boggling how many lethal or life-threatening diseases are now pretty easy to treat. I studied disorders like aplastic anemia, which was very fatal. Without treatment, patients would die within a year. Now, over 95% are cured. Another classic examples is chronic myeloid leukemia disorder. Back when I was a fellow, the median survival for CML was maybe 4 to 6 years. Now, Kareem Abdul Jabbar has had this[for about 15 years]. Also a lot of hematologic malignancies are being cured with immunotherapy approaches. We’ve figured out the pathophysiology of a lot of diseases, and there are incredible genetic diagnostic assays.
Q: What was your father’s relationship with ASH?
Dr. Robert A. Brodsky: The first ASH meeting was 1958 in Atlantic City, New Jersey. There were 300 hematologists there, and my dad was one of them. We’re going to have over 30,000 people in San Diego, which is a record, and another 5,000 or 6,000 virtually.
Q: As ASH president, what are your biggest accomplishments when it comes to addressing the shortage of hematologists and other issues?
Dr. Robert A. Brodsky: ASH is investing $19 million to develop fellowships with a focus on hematology.* This is going to put lots of new hematologists into the workforce over the next 5 to 10 years. We’ve also been working on the Maintenance of Certification [MOC] process to make it less onerous on physicians. It’s really a bad process, and it’s not just ASH [that’s complaining], it’s all of medicine. We’re hearing this from GI, endocrine, renal and the general internists.
[In a September 2023 letter to the American Board of Internal Medicine’s president and chief officer, Dr. Brodsky wrote that “ASH continues to support the importance of lifelong learning for hematologists via a program that is evidence-based, relevant to one’s practice, and transparent; however, these three basic requirements are not met by the current ABIM MOC program.” ASH is calling for a new and reformed MOC program.]
Q: What convinced ASH to expand its journals by adding Blood Neoplasia and Blood Vessels, Thrombosis & Hemostasis?
Dr. Robert A. Brodsky: ASH has two flagship journals right now, Blood and Blood Advances, and they’re both very competitive, high-impact journals. It turns out there’s not enough room to publish all the new science, and they end up rejecting the majority of the submissions that come to them. We decided to keep these journals in the ASH family because there’s some fantastic clinical trials and science that would be going elsewhere.
Dr. Brodsky’s sons both have medical degrees: Brett Brodsky, DO, is a resident at Virginia Commonwealth University who plans to become a sports medicine specialist, and Max Brodsky, MD, is a second-year fellow in hematology at Johns Hopkins University.
In an interview, Max Brodsky, MD, talked about the roots of his family’s dedication to caring for others.
Q: What drew you to hematology?
Dr. Max Brodsky: I’ve watched both my dad and my grandfather be leaders in the field as both physicians and scientists, and that was very inspirational for me to see. And I went to a medical school [Drexel University College of Medicine] that my dad went to and where my grandfather was on faculty. That was like walking in their footsteps in a major way.
Q: What do you hope to focus on as a hematologist?
Dr. Max Brodsky: I’m still working through that, but I am really interested in thrombotic thrombocytopenic purpura. Patients used to not be able to survive their initial episodes, but now we have good treatments and are able to follow them as outpatients. With this whole cohort of patients that are surviving, we’re seeing that they have more health problems — more heart disease, more strokes and kidney disease. There’s a whole growing field exploring how to treat these patients for their lifespan.
Q: How do you deal with the reality that more of your patients will die than in some other medical fields?
Dr. Max Brodsky: It is challenging, but I also see those moments as opportunities to support patients and families. I’m good at connecting to patients and families who are in scary situations. I’ve always had that skill of putting people at ease, making people feel calm, knowing that they can trust me, and I have their best interests in mind.
Q: Why do you think your family is so committed to medicine?
Dr. Max Brodsky: We’re Jewish, and looking to help the world is one of the main core values of Judaism. The Torah expects us to make this world better. Actually, my great-grandfather Max, whom I’m named after, used to dig tunnels to help people escape Ukraine and get to freedom. He was always looking to help others as well. My great-grandmother was shot crossing the border escaping from Ukraine, and he carried her the whole way to the boat. They lived in very poor West Philadelphia and poured everything into my grandfather. He became a great doctor, and his sons and his grandchildren are in medicine today.
*Correction, 12/11: A previous version of this story misstated the amount of ASH’s $19 million investment in developing fellowships with a focus on hematology.
FROM ASH 2023
Study confirms small blood cancer risk from CT scans
The findings, published online in Nature Medicine, are based on more than 1.3 million CT scans in nearly 900,000 people younger than 22 years old when scanned.
This study makes a “significant contribution to the understanding of the effects of ionizing radiation, specifically x-rays, on the human body at the levels of radiation exposure encountered in diagnostic CT procedures,” Peter Marsden, PhD, and Jim Thurston, radiation protection experts at Dorset County (England) Hospital, NHS Foundation Trust, said in a press release from the U.K. nonprofit Science Media Centre.
These findings highlight levels of risk that “align with those currently estimated and do not suggest that the use of CT carries a greater risk than previously thought,” Dr. Marsden and Thurston said.
Exposure to moderate- (≥ 100 mGy) to high-dose (≥ 1 Gy) ionizing radiation is a well-established risk factor for leukemia in both children and adults. However, the risk associated with low-dose exposure (< 100 mGy) typically associated with diagnostic CT exams in children and teens remains unclear.
The current study, coordinated by the International Agency for Research on Cancer, aimed to improve direct estimates of cancer risk from low-dose radiation exposure from CT scans performed in childhood and adolescence. The researchers estimated radiation doses to the active bone marrow based on body part scanned, patient characteristics, time period, and inferred CT technical parameters.
A total of 790 hematologic malignancies, including lymphoid and myeloid malignancies, were identified during follow-up. More than half (51%) of the cases were diagnosed in people under age 20 and 88.5% were diagnosed in people under age 30 years.
Overall, the observational study found a nearly twofold excess risk of all hematologic malignancies per 100 mGy in children, adolescents, and young adults, with similar risk estimates observed for lymphoid and myeloid cancers. The excess relative risk for hematologic malignancies increased as the number of CT exams increased – with risk rising by 43% per exam.
The results of this study “strengthen the findings from previous low-dose studies of a consistent and robust dose-related increased risk of radiation-induced hematological malignancies” and highlight the importance of optimizing doses in this patient population, study author Elisabeth Cardis, PhD, with the Barcelona Institute for Global Health, and colleagues concluded.
Sarah McQuaid, PhD, chair of the nuclear medicine special interest group, Institute of Physics and Engineering in Medicine, York, England, agreed.
“This publication indicates that there could be a small cancer risk from CT scans in young people, but it is important for this to be viewed in the context of the substantial benefit these scans bring, due to the important diagnostic information they provide,” Dr. McQuaid said in the press release. Overall, “the number of patients whose medical care will have been improved from these CT scans will have been very high, and lives undoubtedly saved as a result.”
The study had no commercial funding. The authors and outside experts reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The findings, published online in Nature Medicine, are based on more than 1.3 million CT scans in nearly 900,000 people younger than 22 years old when scanned.
This study makes a “significant contribution to the understanding of the effects of ionizing radiation, specifically x-rays, on the human body at the levels of radiation exposure encountered in diagnostic CT procedures,” Peter Marsden, PhD, and Jim Thurston, radiation protection experts at Dorset County (England) Hospital, NHS Foundation Trust, said in a press release from the U.K. nonprofit Science Media Centre.
These findings highlight levels of risk that “align with those currently estimated and do not suggest that the use of CT carries a greater risk than previously thought,” Dr. Marsden and Thurston said.
Exposure to moderate- (≥ 100 mGy) to high-dose (≥ 1 Gy) ionizing radiation is a well-established risk factor for leukemia in both children and adults. However, the risk associated with low-dose exposure (< 100 mGy) typically associated with diagnostic CT exams in children and teens remains unclear.
The current study, coordinated by the International Agency for Research on Cancer, aimed to improve direct estimates of cancer risk from low-dose radiation exposure from CT scans performed in childhood and adolescence. The researchers estimated radiation doses to the active bone marrow based on body part scanned, patient characteristics, time period, and inferred CT technical parameters.
A total of 790 hematologic malignancies, including lymphoid and myeloid malignancies, were identified during follow-up. More than half (51%) of the cases were diagnosed in people under age 20 and 88.5% were diagnosed in people under age 30 years.
Overall, the observational study found a nearly twofold excess risk of all hematologic malignancies per 100 mGy in children, adolescents, and young adults, with similar risk estimates observed for lymphoid and myeloid cancers. The excess relative risk for hematologic malignancies increased as the number of CT exams increased – with risk rising by 43% per exam.
The results of this study “strengthen the findings from previous low-dose studies of a consistent and robust dose-related increased risk of radiation-induced hematological malignancies” and highlight the importance of optimizing doses in this patient population, study author Elisabeth Cardis, PhD, with the Barcelona Institute for Global Health, and colleagues concluded.
Sarah McQuaid, PhD, chair of the nuclear medicine special interest group, Institute of Physics and Engineering in Medicine, York, England, agreed.
“This publication indicates that there could be a small cancer risk from CT scans in young people, but it is important for this to be viewed in the context of the substantial benefit these scans bring, due to the important diagnostic information they provide,” Dr. McQuaid said in the press release. Overall, “the number of patients whose medical care will have been improved from these CT scans will have been very high, and lives undoubtedly saved as a result.”
The study had no commercial funding. The authors and outside experts reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The findings, published online in Nature Medicine, are based on more than 1.3 million CT scans in nearly 900,000 people younger than 22 years old when scanned.
This study makes a “significant contribution to the understanding of the effects of ionizing radiation, specifically x-rays, on the human body at the levels of radiation exposure encountered in diagnostic CT procedures,” Peter Marsden, PhD, and Jim Thurston, radiation protection experts at Dorset County (England) Hospital, NHS Foundation Trust, said in a press release from the U.K. nonprofit Science Media Centre.
These findings highlight levels of risk that “align with those currently estimated and do not suggest that the use of CT carries a greater risk than previously thought,” Dr. Marsden and Thurston said.
Exposure to moderate- (≥ 100 mGy) to high-dose (≥ 1 Gy) ionizing radiation is a well-established risk factor for leukemia in both children and adults. However, the risk associated with low-dose exposure (< 100 mGy) typically associated with diagnostic CT exams in children and teens remains unclear.
The current study, coordinated by the International Agency for Research on Cancer, aimed to improve direct estimates of cancer risk from low-dose radiation exposure from CT scans performed in childhood and adolescence. The researchers estimated radiation doses to the active bone marrow based on body part scanned, patient characteristics, time period, and inferred CT technical parameters.
A total of 790 hematologic malignancies, including lymphoid and myeloid malignancies, were identified during follow-up. More than half (51%) of the cases were diagnosed in people under age 20 and 88.5% were diagnosed in people under age 30 years.
Overall, the observational study found a nearly twofold excess risk of all hematologic malignancies per 100 mGy in children, adolescents, and young adults, with similar risk estimates observed for lymphoid and myeloid cancers. The excess relative risk for hematologic malignancies increased as the number of CT exams increased – with risk rising by 43% per exam.
The results of this study “strengthen the findings from previous low-dose studies of a consistent and robust dose-related increased risk of radiation-induced hematological malignancies” and highlight the importance of optimizing doses in this patient population, study author Elisabeth Cardis, PhD, with the Barcelona Institute for Global Health, and colleagues concluded.
Sarah McQuaid, PhD, chair of the nuclear medicine special interest group, Institute of Physics and Engineering in Medicine, York, England, agreed.
“This publication indicates that there could be a small cancer risk from CT scans in young people, but it is important for this to be viewed in the context of the substantial benefit these scans bring, due to the important diagnostic information they provide,” Dr. McQuaid said in the press release. Overall, “the number of patients whose medical care will have been improved from these CT scans will have been very high, and lives undoubtedly saved as a result.”
The study had no commercial funding. The authors and outside experts reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NATURE MEDICINE
FDA’s Project Optimus aims to transform early cancer research
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
AT SITC 2023
FDA approves bosutinib for children with CML
The agency also approved new 50-mg and 100-mg capsules to help treat children.
For newly diagnosed disease, the dose is 300 mg/m2 once daily with food. For resistant/intolerant disease, the dose is 400 mg/m2 once daily. For children who cannot swallow capsules, the contents can be mixed into applesauce or yogurt, the FDA said in a press release announcing the approval.
The tyrosine kinase inhibitor (TKI) was previously approved for adults. Three other TKIs were previously approved for pediatric CML.
The approval was based on the BCHILD trial, a pediatric dose-finding study involving patients aged 1 year or older. Among the 21 children with newly diagnosed chronic phase, Ph+ CML treated with 300 mg/m2, the rate of major cytogenetic response was 76.2%, the rate of complete cytogenetic response was 71.4%, and the rate of major molecular response rate was 28.6% over a median duration of 14.2 months.
Among the 28 children with relapsed/intolerant disease treated with up to 400 mg/m2, the rate of major cytogenetic response was 82.1%, the rate of complete cytogenetic response was 78.6%, and the rate of major molecular response was 50% over a median duration of 23.2 months. Among the 14 patients who had a major molecular response, two lost it – one after 13.6 months of treatment, and the other after 24.7 months of treatment.
Adverse events that occurred in 20% or more of children included diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation. Overall, 45% or more of patients experienced an increase in creatinine, alanine aminotransferase, or aspartate aminotransferase levels, or a decrease in white blood cell count or platelet count.
The full labeling information is available online.
A version of this article first appeared on Medscape.com.
The agency also approved new 50-mg and 100-mg capsules to help treat children.
For newly diagnosed disease, the dose is 300 mg/m2 once daily with food. For resistant/intolerant disease, the dose is 400 mg/m2 once daily. For children who cannot swallow capsules, the contents can be mixed into applesauce or yogurt, the FDA said in a press release announcing the approval.
The tyrosine kinase inhibitor (TKI) was previously approved for adults. Three other TKIs were previously approved for pediatric CML.
The approval was based on the BCHILD trial, a pediatric dose-finding study involving patients aged 1 year or older. Among the 21 children with newly diagnosed chronic phase, Ph+ CML treated with 300 mg/m2, the rate of major cytogenetic response was 76.2%, the rate of complete cytogenetic response was 71.4%, and the rate of major molecular response rate was 28.6% over a median duration of 14.2 months.
Among the 28 children with relapsed/intolerant disease treated with up to 400 mg/m2, the rate of major cytogenetic response was 82.1%, the rate of complete cytogenetic response was 78.6%, and the rate of major molecular response was 50% over a median duration of 23.2 months. Among the 14 patients who had a major molecular response, two lost it – one after 13.6 months of treatment, and the other after 24.7 months of treatment.
Adverse events that occurred in 20% or more of children included diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation. Overall, 45% or more of patients experienced an increase in creatinine, alanine aminotransferase, or aspartate aminotransferase levels, or a decrease in white blood cell count or platelet count.
The full labeling information is available online.
A version of this article first appeared on Medscape.com.
The agency also approved new 50-mg and 100-mg capsules to help treat children.
For newly diagnosed disease, the dose is 300 mg/m2 once daily with food. For resistant/intolerant disease, the dose is 400 mg/m2 once daily. For children who cannot swallow capsules, the contents can be mixed into applesauce or yogurt, the FDA said in a press release announcing the approval.
The tyrosine kinase inhibitor (TKI) was previously approved for adults. Three other TKIs were previously approved for pediatric CML.
The approval was based on the BCHILD trial, a pediatric dose-finding study involving patients aged 1 year or older. Among the 21 children with newly diagnosed chronic phase, Ph+ CML treated with 300 mg/m2, the rate of major cytogenetic response was 76.2%, the rate of complete cytogenetic response was 71.4%, and the rate of major molecular response rate was 28.6% over a median duration of 14.2 months.
Among the 28 children with relapsed/intolerant disease treated with up to 400 mg/m2, the rate of major cytogenetic response was 82.1%, the rate of complete cytogenetic response was 78.6%, and the rate of major molecular response was 50% over a median duration of 23.2 months. Among the 14 patients who had a major molecular response, two lost it – one after 13.6 months of treatment, and the other after 24.7 months of treatment.
Adverse events that occurred in 20% or more of children included diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation. Overall, 45% or more of patients experienced an increase in creatinine, alanine aminotransferase, or aspartate aminotransferase levels, or a decrease in white blood cell count or platelet count.
The full labeling information is available online.
A version of this article first appeared on Medscape.com.
Antibody shows promise in preventing GVHD
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
FROM SCIENCE TRANSLATIONAL MEDICINE
ESMO helps hematologists assess new cancer drugs
It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.
Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.
On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.
The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.
The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.
To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.
Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.
The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.
ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.
It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.
Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.
On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.
The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.
The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.
To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.
Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.
The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.
ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.
It consists of 11 2- to 3-page forms with checklists to grade treatment trials on the extent to which they meet efficacy and safety thresholds. Each of the 11 forms covers a specific trial scenario, such as a randomized controlled trial with curative intent or a trial of a therapy that is not likely to be curative with a primary endpoint of overall survival.
Treatments with curative intent are graded A, B, or C, while treatments in the noncurative setting are graded on a descending scale from 5 to 1. Scores of A and B in the curative setting and 5 and 4 in the noncurative setting represent substantial benefit.
On the form for RCTs with curative intent, for instance, a survival improvement of 5% or more garners an A but an improvement of less than 3% gets a C. Scores are also annotated for serious acute and/or persistent toxicity if present.
The tool, dubbed the ESMO-MCBS:H (European Society for Medical Oncology Magnitude of Clinical Benefit Scale: Hematology), is explained in an article published in Annals of Oncology. The evaluation forms are available online.
The idea behind the work is to help health care professionals and others to more “accurately assess the value of and prioritise therapies for patients with blood cancers. For clinicians, ESMO-MCBS:H will aid in their clinical decision-making and in the development of evidence-based practice and guidelines,” ESMO said in a press release.
To develop ESMO-MCBS:H, the group tailored its tool for evaluating solid tumor therapies, the ESMO-MCBS, to account for the sometimes different endpoints used in hematologic malignancy trials and the very indolent nature of some blood cancers, such as follicular lymphoma, which hampers development of mature data.
Specific changes include adding a new evaluation form to grade single-arm trials with curative intent, such as those used for CAR-T-cell therapies; incorporating molecular surrogate endpoints used in CML trials; and adding a way to grade outcomes for indolent cancers, among others.
The development process included applying the solid tumor tool to 80 blood cancer studies to identify shortcomings and improve its applicability. The final tool was field tested with 51 international experts from EHA and ESMO who largely agreed on the reasonableness of the trial scores.
ESMO said it expects ESMO-MCBS:H will be useful. The solid tumor tool, first published in 2015, is used by the World Health Organization to screen medications for its essential medicines list as well as by ESMO to generate guidelines and oncology centers across Europe to help with resource allocation decisions.
FROM ANNALS OF ONCOLOGY