Immuno-oncology

The Cost of Oncology Drugs: A Pharmacy Perspective, Part 1, appeared in the Federal Practitioner February 2016 special issue “Best Practices in Hematology and Oncology” and can be accessed here.

Health care costs are the fastest growing financial segment of the U.S. economy. The cost of medications, especially those for treating cancer, is the leading cause of increased health care spending.¹ Until recently, the discussion of the high costs of cancer treatment was rarely made public.

Part 1 of this article focused on the emerging discussion of the financial impact of high-cost drugs in the U.S. Part 2 will focus on the drivers of increasing oncology drug costs and the challenges high-cost medications pose for the VA. The article also will review the role of the VA Pharmacy Benefits Management Service (PBM) in evaluating new oncology agents. Also presented are the clinical guidance tools designed to aid the clinician in the cost-effective use of these agents and results of a nationwide survey of VA oncology pharmacists regarding the use of cost-containment strategies.

Cost Drivers

Many factors are driving increased oncology drug costs within the VA. Although the cost of individual drugs has the largest impact on the accelerating cost of treating each patient, other clinical and social factors may play a role.

Increasing Cost of Individual Drugs

Drug pricing is not announced until after FDA approval. Oncology drugs at the high end of the cost spectrum are rarely curative and often add only weeks or months to overall survival (OS), the gold standard. Current clinical trial design often uses progression free survival (PFS) as the primary endpoint, which makes the use of traditional pharmacoeconomic determinations of value difficult. In addition, many new drugs are first in class and/or have narrow indications that preclude competition from other drugs. Although addressing the issue of the market price for drugs seems to be one that is not controllable, there is increasing demand for drug pricing reform.²

Many believe drug prices should be linked directly to clinical benefit. In a recent article, Goldstein and colleagues proposed establishing a value-based price for necitumumab based on clinical benefit, prior to FDA approval.³ When this analysis was done, necitumumab was pending FDA approval in combination with cisplatin and gemcitabine for the treatment of squamous carcinoma of the lung. Using clinical data from the SQUIRE trial on which FDA approval was based, the addition of necitumumab to the chemotherapy regimen led to an incremental survival benefit of 0.15 life-years and 0.11 quality-adjusted life-years (QALY).⁴ Using a Markov model to evaluate cost-effectiveness, these authors established that the price of necitumumab should be from $563 to $1,309 per cycle. Necitumumab was approved by the FDA on November 24, 2015, with the VA acquisition cost, as of May 2016, at $6,100 per cycle.

Lack of Generic Products

The approval of generic alternatives for targeted oncology agents should reduce the cost of treating oncology patients. However, since imatinib was approved in May 2001, no single targeted agent had become available as a generic until February 1, 2016, when generic imatinib was made available in the U.S. following approval by the FDA. Currently, generic imatinib is not used in the VA due to lack of Federal Supply Schedule (FSS) contract pricing, which leads to a generic cost that is much higher than the brand-name drug, Gleevec ($6,127 per month vs $9,472 per month for the generic). The reality is that many older agents have steadily increased in price, outpacing inflation (Table 1).⁵

Aging U.S. Population

Advancing age is the most common risk factor for cancer, leading to an increase in the incidence and treatment of cancer. Because many newer agents are considered easier to tolerate than are traditional cytotoxic chemotherapy, clinicians have become more comfortable treating elderly patients, and geriatric oncology has become an established subspecialty within oncology.

Changing Treatment Paradigms

The use of targeted therapies is changing the paradigm from the acute treatment of cancer to chronic cancer management. Most targeted therapies are continued until disease progression or toxicity, leading to chronic, open-ended treatment. This approach is in contrast to older treatment approaches such as chemotherapy, which is often given for a limited duration followed by observation. When successful, chronic treatment with targeted agents can lead to unanticipated high costs. The following current cases at the VA San Diego Healthcare System illustrate this point:

• Renal cell carcinoma: 68-year-old man diagnosed in 2005 with a recurrence in 2012

- High-dose interleukin-2 (2 cycles); sunitinib (3.3 years); pazopanib (2 months); everolimus (2 months); sorafenib (3 months); axitinib (7 months)

• Cutaneous T-cell lymphoma: 68-year-old man started romidepsin September 22, 2010

The rate of FDA approval for oncology drugs has been accelerating rapidly in the past 15 years. Sequential therapies beyond second-line therapy are common as more agents become available. Table 2 shows FDA approval for all cancer drugs by decade.

As researchers continue to better understand the many pathways involved with the development and progression of cancer, they are beginning to combine multiple targeted agents to augment response rates, prolong survival, and reduce the potential for resistance. Recent combination regimens approved by the FDA include dabrafenib plus trametinib (January 2014), and ipilimumab plus nivolumab (October 2015), both for the treatment of melanoma. In November 2015, ixazomib was FDA approved to be used in combination with lenalidomide for multiple myeloma. Many more combination regimens are currently in clinical trials, and more combinations are expected to receive FDA approval. It is easy to see how the combination of multiple expensive agents with the prospect of prolonged therapy has the potential to increase the cost of many regimens to well over $100,000 per year.

Maintenance therapy is used to prolong PFS for patients receiving an excellent response to primary therapy. For example, VA costs for maintenance regimens include lenalidomide 10 mg daily: $8,314 for 28 days equals $216,177 for 2 years; bortezomib 1.3 mg/m² (2.6 mg) q: 2 weeks equals $60,730 for 2 years (includes waste as bortezomib 3.5-mg vials do not a contain preservative and must be discarded within 8 hours of preparation); and rituximab 800 mg q: 2 months equals $47,635 for 2 years.

Until recently, immunotherapy for cancer was limited to melanoma and renal cell carcinoma using interleukin-2 (aldesleukin) and interferon alfa. However, the immergence of new immunotherapies, such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have expanded the role of immunotherapy to many other, more common, malignancies, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, and many more.

Most randomized clinical trials study drugs as second- or occasionally third-line therapy. However, many patients continue to be treated beyond the third-line setting, often without evidence-based data to support potential benefit. Patients often place value on treatments unlikely to work so as not to give up hope. These “hopeful gambles,” even with the potential of significant toxicity and decreased quality of life (QOL), are common in cancer treatment.⁶ In addition, oncologists often overestimate the clinical benefit when considering additional therapy in this setting.⁷

Influx of New Patients

Outside the VHA setting, the financial burden of cancer treatment has led to an influx of new patients transferring care to the VHA to reduce out-of-pocket expenses. Because private insurance copays for oral agents are increasing, many reaching 20% to 30%, out-of-pocket expenses for medications can reach several thousand dollars per month. Patients often change insurance plans due to changing jobs or to decrease cost, or employers may change plans to save money, which may significantly alter or discontinue coverage. Patients often request that the VA provide medication while continuing to see only their private oncologist. This practice should be discouraged because the VA, without clinical involvement, may supply drugs for inappropriate indications. In addition, VA providers writing prescriptions for medications without personally following patients may be liable for poor outcomes.

VA PBM Services

Prior to 1995, the VA was a much criticized and poorly performing health care system that had experienced significant budget cuts, forcing many veterans to seek care outside the VA. Then beginning in 1995, a remarkable transformation occurred, which modernized and improved the VA into a system that consistently outperforms the private sector in quality of care, patient safety, patient satisfaction, all at a lower cost.⁸ The story of the VA’s transformation has been well chronicled by Phillip Longman.⁹

Under the direction of VA Under Secretary for Health Kenneth Kizer, MD, MPH, VA established PBM Clinical Services to develop and maintain the National Drug Formulary, create clinical guidance documents, and manage drug costs and utilization. A recent article by Heron and Geraci examined the functions and role of the VA PBM in controlling oncology drug costs.¹⁰ The following is a brief review of several documents and VA PBM responsibilities as reviewed by Heron and Geraci.

VA National Formulary

Prior to the establishment of the VA National Formulary in 1995, each VA maintained its own formulary, which led to extreme variability in drug access across the country. When a patient accessed care at different VAMCs, it was common for the patient’s medications to be changed based on the specific facility formulary. This practice led to many potential problems, such as lack of clinical benefit and potentially increased or new toxicities, and led to extra hospital visits for monitoring and adjustment of medications.

In contrast, the VA National Formulary now offers a uniform pharmacy benefit to all veterans by reducing variation in access to drugs. In addition, using preferred agents in each drug class provides VA with additional leverage when contracting with drug suppliers to reduce prices across the entire VA system.

Many oncology agents are not included on the VA National Formulary due to cost and the potential for off-label use. However, the formulary status of oncology agents in no way limits access or the availability of any oncology drug for appropriate patients. In fact, nonformulary approval requests work as a mechanism for review to ensure that these agents are used properly in the subset of patients who are most likely to benefit.

The PBM assesses all new oncology drugs for value and potential use within the VA, as well as cost impact. Following this assessment, various clinical guidance documents may be developed that are intended to guide clinicians in the proper use of medications for veterans. All documents prepared by the PBM undergo an extensive peer review by the Medical Advisory Panel and other experts in the field.

Drug Monographs

A drug monograph is a comprehensive, evidence-based drug review that summarizes efficacy and safety based on clinical trial data published in peer-reviewed journals, abstracts, and/or FDA Medical Review transcripts. Cost-effectiveness analysis is included if available.

Criteria for Use

Criteria for Use (CFU) are developed for drugs considered to be at high risk for inappropriate use or with safety concerns. The purpose of the CFU is to select patients most likely to benefit from these agents by using clinical criteria, which may qualify or eliminate a patient for treatment. National CFUs are available on the national PBM website. Local CFUs are often written and shared among oncology pharmacists via the VA oncology pharmacist listserv.

Abbreviated Reviews

Similar to drug monographs, abbreviated reviews are much shorter and focus on the relevant clinical sections of the drug monograph necessary for clinical or formulary decision making.

National Acquisition Center

The National Acquisition Center (NAC) is the pharmaceutical contracting mechanism for the VA and works closely with the PBM.⁵ The NAC pursues significant drug price reductions for the VA based on many strategies. Public Law 102-585 ensures that certain government agencies, including the VA, receive special discounts on pharmaceuticals, which is at least a 24% discount from the nonfederal Average Manufacturer Price. This is known as the Federal Supply Schedule (FSS) and/or Big 4 pricing. In addition, bulk purchases and performance-based incentive agreements can lead to substantial local discounts. By working with specific drug distribution and warehouse contractors, the NAC assures ready access to drugs for VA patients. The NAC also allows for an efficient drug inventory process, thus reducing inventory management costs.

Guidance Documents

In 2012, the VA Oncology Field Advisory Committee (FAC) created the High Cost Oncology Drug Work Group to address the impact of high-cost oncology drugs within the VA.¹¹ This work group was composed of VA oncologists and pharmacists whose efforts resulted in 5 guidance documents designed to reduce drug costs by optimizing therapy and reducing waste: (1) Dose Rounding in Oncology; (2) Oral Anticancer Drugs Dispensing and Monitoring; (3) Oncology Drug Table: Recommended Dispensing and Monitoring; (4) Chemotherapy Review Committee Process; and (5) Determining Clinical Benefit of High Cost Oncology Drugs. Reviews of 2 of these documents follows.

Determining Clinical Benefit of High Cost Oncology Drugs provides a decision tool to aid members of the oncology health care team in optimizing patient outcomes while attempting to obtain the greatest value from innovative therapies. When a high-cost or off-label request is made for a particular patient, using this process encourages thoughtful and evidence-based use of the drug by considering all clinical evidence in addition to the FDA-approved indication. Finally, a drug’s safety profile in relation to the indication, therapeutic goal, and specific patient characteristics and desires are integrated into a final decision to determine the appropriateness of the therapeutic intervention for the patient.

Oncology Drug Table: Recommended Dispensing and Monitoring contains a list of oral oncology drugs and includes recommendations for dispensing amount, adverse effects, laboratory monitoring, formulary status, approval requirements, and monthly cost of each agent based on the current NAC pricing.⁵ Cost awareness is critical when comparing alternative treatment options to minimize cost when treatments with similar benefits are considered. Most VA oncologists do not have easy access to the cost of various treatments and can be surprised about how expensive many common regimens cost. The costs listed in this document are updated about every 3 months.

Conclusion

Using newer, expensive targeted oncology agents in a cost-effective manner must be a proactive, collaborative, and multidisciplinary process. Pharmacists should not be solely responsible for monitoring and controlling high-cost treatments. Well-informed, evidence-based decisions are needed to ensure expensive agents are used in the subset of patients who are most likely to benefit. Clinical tools addressing value should be used to aid in appropriate and cost-effective treatment plans using drug monographs and CFUs, VHA Guidance on Determining Clinical Benefit of High Cost Oncology Drugs, and the Oral Chemotherapy Dispensing and Monitoring Reference, among other resources. Due to the subjective nature of value in medicine, agreeing on policy will have many challenges, such as how to place a value on various gains in overall survival, progression free survival, response rates, and QOL.

eAppendix

The Cost of Oncology Drugs: A Pharmacy Perspective, Part 1, appeared in the Federal Practitioner February 2016 special issue “Best Practices in Hematology and Oncology” and can be accessed here.

Health care costs are the fastest growing financial segment of the U.S. economy. The cost of medications, especially those for treating cancer, is the leading cause of increased health care spending.¹ Until recently, the discussion of the high costs of cancer treatment was rarely made public.

Part 1 of this article focused on the emerging discussion of the financial impact of high-cost drugs in the U.S. Part 2 will focus on the drivers of increasing oncology drug costs and the challenges high-cost medications pose for the VA. The article also will review the role of the VA Pharmacy Benefits Management Service (PBM) in evaluating new oncology agents. Also presented are the clinical guidance tools designed to aid the clinician in the cost-effective use of these agents and results of a nationwide survey of VA oncology pharmacists regarding the use of cost-containment strategies.

Cost Drivers

Many factors are driving increased oncology drug costs within the VA. Although the cost of individual drugs has the largest impact on the accelerating cost of treating each patient, other clinical and social factors may play a role.

Increasing Cost of Individual Drugs

Drug pricing is not announced until after FDA approval. Oncology drugs at the high end of the cost spectrum are rarely curative and often add only weeks or months to overall survival (OS), the gold standard. Current clinical trial design often uses progression free survival (PFS) as the primary endpoint, which makes the use of traditional pharmacoeconomic determinations of value difficult. In addition, many new drugs are first in class and/or have narrow indications that preclude competition from other drugs. Although addressing the issue of the market price for drugs seems to be one that is not controllable, there is increasing demand for drug pricing reform.²

Many believe drug prices should be linked directly to clinical benefit. In a recent article, Goldstein and colleagues proposed establishing a value-based price for necitumumab based on clinical benefit, prior to FDA approval.³ When this analysis was done, necitumumab was pending FDA approval in combination with cisplatin and gemcitabine for the treatment of squamous carcinoma of the lung. Using clinical data from the SQUIRE trial on which FDA approval was based, the addition of necitumumab to the chemotherapy regimen led to an incremental survival benefit of 0.15 life-years and 0.11 quality-adjusted life-years (QALY).⁴ Using a Markov model to evaluate cost-effectiveness, these authors established that the price of necitumumab should be from $563 to $1,309 per cycle. Necitumumab was approved by the FDA on November 24, 2015, with the VA acquisition cost, as of May 2016, at $6,100 per cycle.

Lack of Generic Products

The approval of generic alternatives for targeted oncology agents should reduce the cost of treating oncology patients. However, since imatinib was approved in May 2001, no single targeted agent had become available as a generic until February 1, 2016, when generic imatinib was made available in the U.S. following approval by the FDA. Currently, generic imatinib is not used in the VA due to lack of Federal Supply Schedule (FSS) contract pricing, which leads to a generic cost that is much higher than the brand-name drug, Gleevec ($6,127 per month vs $9,472 per month for the generic). The reality is that many older agents have steadily increased in price, outpacing inflation (Table 1).⁵

Aging U.S. Population

Advancing age is the most common risk factor for cancer, leading to an increase in the incidence and treatment of cancer. Because many newer agents are considered easier to tolerate than are traditional cytotoxic chemotherapy, clinicians have become more comfortable treating elderly patients, and geriatric oncology has become an established subspecialty within oncology.

Changing Treatment Paradigms

The use of targeted therapies is changing the paradigm from the acute treatment of cancer to chronic cancer management. Most targeted therapies are continued until disease progression or toxicity, leading to chronic, open-ended treatment. This approach is in contrast to older treatment approaches such as chemotherapy, which is often given for a limited duration followed by observation. When successful, chronic treatment with targeted agents can lead to unanticipated high costs. The following current cases at the VA San Diego Healthcare System illustrate this point:

• Renal cell carcinoma: 68-year-old man diagnosed in 2005 with a recurrence in 2012

- High-dose interleukin-2 (2 cycles); sunitinib (3.3 years); pazopanib (2 months); everolimus (2 months); sorafenib (3 months); axitinib (7 months)

• Cutaneous T-cell lymphoma: 68-year-old man started romidepsin September 22, 2010

The rate of FDA approval for oncology drugs has been accelerating rapidly in the past 15 years. Sequential therapies beyond second-line therapy are common as more agents become available. Table 2 shows FDA approval for all cancer drugs by decade.

As researchers continue to better understand the many pathways involved with the development and progression of cancer, they are beginning to combine multiple targeted agents to augment response rates, prolong survival, and reduce the potential for resistance. Recent combination regimens approved by the FDA include dabrafenib plus trametinib (January 2014), and ipilimumab plus nivolumab (October 2015), both for the treatment of melanoma. In November 2015, ixazomib was FDA approved to be used in combination with lenalidomide for multiple myeloma. Many more combination regimens are currently in clinical trials, and more combinations are expected to receive FDA approval. It is easy to see how the combination of multiple expensive agents with the prospect of prolonged therapy has the potential to increase the cost of many regimens to well over $100,000 per year.

Maintenance therapy is used to prolong PFS for patients receiving an excellent response to primary therapy. For example, VA costs for maintenance regimens include lenalidomide 10 mg daily: $8,314 for 28 days equals $216,177 for 2 years; bortezomib 1.3 mg/m² (2.6 mg) q: 2 weeks equals $60,730 for 2 years (includes waste as bortezomib 3.5-mg vials do not a contain preservative and must be discarded within 8 hours of preparation); and rituximab 800 mg q: 2 months equals $47,635 for 2 years.

Until recently, immunotherapy for cancer was limited to melanoma and renal cell carcinoma using interleukin-2 (aldesleukin) and interferon alfa. However, the immergence of new immunotherapies, such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have expanded the role of immunotherapy to many other, more common, malignancies, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, and many more.

Most randomized clinical trials study drugs as second- or occasionally third-line therapy. However, many patients continue to be treated beyond the third-line setting, often without evidence-based data to support potential benefit. Patients often place value on treatments unlikely to work so as not to give up hope. These “hopeful gambles,” even with the potential of significant toxicity and decreased quality of life (QOL), are common in cancer treatment.⁶ In addition, oncologists often overestimate the clinical benefit when considering additional therapy in this setting.⁷

Influx of New Patients

Outside the VHA setting, the financial burden of cancer treatment has led to an influx of new patients transferring care to the VHA to reduce out-of-pocket expenses. Because private insurance copays for oral agents are increasing, many reaching 20% to 30%, out-of-pocket expenses for medications can reach several thousand dollars per month. Patients often change insurance plans due to changing jobs or to decrease cost, or employers may change plans to save money, which may significantly alter or discontinue coverage. Patients often request that the VA provide medication while continuing to see only their private oncologist. This practice should be discouraged because the VA, without clinical involvement, may supply drugs for inappropriate indications. In addition, VA providers writing prescriptions for medications without personally following patients may be liable for poor outcomes.

VA PBM Services

Prior to 1995, the VA was a much criticized and poorly performing health care system that had experienced significant budget cuts, forcing many veterans to seek care outside the VA. Then beginning in 1995, a remarkable transformation occurred, which modernized and improved the VA into a system that consistently outperforms the private sector in quality of care, patient safety, patient satisfaction, all at a lower cost.⁸ The story of the VA’s transformation has been well chronicled by Phillip Longman.⁹

Under the direction of VA Under Secretary for Health Kenneth Kizer, MD, MPH, VA established PBM Clinical Services to develop and maintain the National Drug Formulary, create clinical guidance documents, and manage drug costs and utilization. A recent article by Heron and Geraci examined the functions and role of the VA PBM in controlling oncology drug costs.¹⁰ The following is a brief review of several documents and VA PBM responsibilities as reviewed by Heron and Geraci.

VA National Formulary

Prior to the establishment of the VA National Formulary in 1995, each VA maintained its own formulary, which led to extreme variability in drug access across the country. When a patient accessed care at different VAMCs, it was common for the patient’s medications to be changed based on the specific facility formulary. This practice led to many potential problems, such as lack of clinical benefit and potentially increased or new toxicities, and led to extra hospital visits for monitoring and adjustment of medications.

In contrast, the VA National Formulary now offers a uniform pharmacy benefit to all veterans by reducing variation in access to drugs. In addition, using preferred agents in each drug class provides VA with additional leverage when contracting with drug suppliers to reduce prices across the entire VA system.

Many oncology agents are not included on the VA National Formulary due to cost and the potential for off-label use. However, the formulary status of oncology agents in no way limits access or the availability of any oncology drug for appropriate patients. In fact, nonformulary approval requests work as a mechanism for review to ensure that these agents are used properly in the subset of patients who are most likely to benefit.

The PBM assesses all new oncology drugs for value and potential use within the VA, as well as cost impact. Following this assessment, various clinical guidance documents may be developed that are intended to guide clinicians in the proper use of medications for veterans. All documents prepared by the PBM undergo an extensive peer review by the Medical Advisory Panel and other experts in the field.

Drug Monographs

A drug monograph is a comprehensive, evidence-based drug review that summarizes efficacy and safety based on clinical trial data published in peer-reviewed journals, abstracts, and/or FDA Medical Review transcripts. Cost-effectiveness analysis is included if available.

Criteria for Use

Criteria for Use (CFU) are developed for drugs considered to be at high risk for inappropriate use or with safety concerns. The purpose of the CFU is to select patients most likely to benefit from these agents by using clinical criteria, which may qualify or eliminate a patient for treatment. National CFUs are available on the national PBM website. Local CFUs are often written and shared among oncology pharmacists via the VA oncology pharmacist listserv.

Abbreviated Reviews

Similar to drug monographs, abbreviated reviews are much shorter and focus on the relevant clinical sections of the drug monograph necessary for clinical or formulary decision making.

National Acquisition Center

The National Acquisition Center (NAC) is the pharmaceutical contracting mechanism for the VA and works closely with the PBM.⁵ The NAC pursues significant drug price reductions for the VA based on many strategies. Public Law 102-585 ensures that certain government agencies, including the VA, receive special discounts on pharmaceuticals, which is at least a 24% discount from the nonfederal Average Manufacturer Price. This is known as the Federal Supply Schedule (FSS) and/or Big 4 pricing. In addition, bulk purchases and performance-based incentive agreements can lead to substantial local discounts. By working with specific drug distribution and warehouse contractors, the NAC assures ready access to drugs for VA patients. The NAC also allows for an efficient drug inventory process, thus reducing inventory management costs.

Guidance Documents

In 2012, the VA Oncology Field Advisory Committee (FAC) created the High Cost Oncology Drug Work Group to address the impact of high-cost oncology drugs within the VA.¹¹ This work group was composed of VA oncologists and pharmacists whose efforts resulted in 5 guidance documents designed to reduce drug costs by optimizing therapy and reducing waste: (1) Dose Rounding in Oncology; (2) Oral Anticancer Drugs Dispensing and Monitoring; (3) Oncology Drug Table: Recommended Dispensing and Monitoring; (4) Chemotherapy Review Committee Process; and (5) Determining Clinical Benefit of High Cost Oncology Drugs. Reviews of 2 of these documents follows.

Determining Clinical Benefit of High Cost Oncology Drugs provides a decision tool to aid members of the oncology health care team in optimizing patient outcomes while attempting to obtain the greatest value from innovative therapies. When a high-cost or off-label request is made for a particular patient, using this process encourages thoughtful and evidence-based use of the drug by considering all clinical evidence in addition to the FDA-approved indication. Finally, a drug’s safety profile in relation to the indication, therapeutic goal, and specific patient characteristics and desires are integrated into a final decision to determine the appropriateness of the therapeutic intervention for the patient.

Oncology Drug Table: Recommended Dispensing and Monitoring contains a list of oral oncology drugs and includes recommendations for dispensing amount, adverse effects, laboratory monitoring, formulary status, approval requirements, and monthly cost of each agent based on the current NAC pricing.⁵ Cost awareness is critical when comparing alternative treatment options to minimize cost when treatments with similar benefits are considered. Most VA oncologists do not have easy access to the cost of various treatments and can be surprised about how expensive many common regimens cost. The costs listed in this document are updated about every 3 months.

Conclusion

Using newer, expensive targeted oncology agents in a cost-effective manner must be a proactive, collaborative, and multidisciplinary process. Pharmacists should not be solely responsible for monitoring and controlling high-cost treatments. Well-informed, evidence-based decisions are needed to ensure expensive agents are used in the subset of patients who are most likely to benefit. Clinical tools addressing value should be used to aid in appropriate and cost-effective treatment plans using drug monographs and CFUs, VHA Guidance on Determining Clinical Benefit of High Cost Oncology Drugs, and the Oral Chemotherapy Dispensing and Monitoring Reference, among other resources. Due to the subjective nature of value in medicine, agreeing on policy will have many challenges, such as how to place a value on various gains in overall survival, progression free survival, response rates, and QOL.

eAppendix

The Cost of Oncology Drugs: A Pharmacy Perspective, Part 1, appeared in the Federal Practitioner February 2016 special issue “Best Practices in Hematology and Oncology” and can be accessed here.

Health care costs are the fastest growing financial segment of the U.S. economy. The cost of medications, especially those for treating cancer, is the leading cause of increased health care spending.¹ Until recently, the discussion of the high costs of cancer treatment was rarely made public.

Part 1 of this article focused on the emerging discussion of the financial impact of high-cost drugs in the U.S. Part 2 will focus on the drivers of increasing oncology drug costs and the challenges high-cost medications pose for the VA. The article also will review the role of the VA Pharmacy Benefits Management Service (PBM) in evaluating new oncology agents. Also presented are the clinical guidance tools designed to aid the clinician in the cost-effective use of these agents and results of a nationwide survey of VA oncology pharmacists regarding the use of cost-containment strategies.

Cost Drivers

Many factors are driving increased oncology drug costs within the VA. Although the cost of individual drugs has the largest impact on the accelerating cost of treating each patient, other clinical and social factors may play a role.

Increasing Cost of Individual Drugs

Drug pricing is not announced until after FDA approval. Oncology drugs at the high end of the cost spectrum are rarely curative and often add only weeks or months to overall survival (OS), the gold standard. Current clinical trial design often uses progression free survival (PFS) as the primary endpoint, which makes the use of traditional pharmacoeconomic determinations of value difficult. In addition, many new drugs are first in class and/or have narrow indications that preclude competition from other drugs. Although addressing the issue of the market price for drugs seems to be one that is not controllable, there is increasing demand for drug pricing reform.²

Many believe drug prices should be linked directly to clinical benefit. In a recent article, Goldstein and colleagues proposed establishing a value-based price for necitumumab based on clinical benefit, prior to FDA approval.³ When this analysis was done, necitumumab was pending FDA approval in combination with cisplatin and gemcitabine for the treatment of squamous carcinoma of the lung. Using clinical data from the SQUIRE trial on which FDA approval was based, the addition of necitumumab to the chemotherapy regimen led to an incremental survival benefit of 0.15 life-years and 0.11 quality-adjusted life-years (QALY).⁴ Using a Markov model to evaluate cost-effectiveness, these authors established that the price of necitumumab should be from $563 to $1,309 per cycle. Necitumumab was approved by the FDA on November 24, 2015, with the VA acquisition cost, as of May 2016, at $6,100 per cycle.

Lack of Generic Products

The approval of generic alternatives for targeted oncology agents should reduce the cost of treating oncology patients. However, since imatinib was approved in May 2001, no single targeted agent had become available as a generic until February 1, 2016, when generic imatinib was made available in the U.S. following approval by the FDA. Currently, generic imatinib is not used in the VA due to lack of Federal Supply Schedule (FSS) contract pricing, which leads to a generic cost that is much higher than the brand-name drug, Gleevec ($6,127 per month vs $9,472 per month for the generic). The reality is that many older agents have steadily increased in price, outpacing inflation (Table 1).⁵

Aging U.S. Population

Advancing age is the most common risk factor for cancer, leading to an increase in the incidence and treatment of cancer. Because many newer agents are considered easier to tolerate than are traditional cytotoxic chemotherapy, clinicians have become more comfortable treating elderly patients, and geriatric oncology has become an established subspecialty within oncology.

Changing Treatment Paradigms

The use of targeted therapies is changing the paradigm from the acute treatment of cancer to chronic cancer management. Most targeted therapies are continued until disease progression or toxicity, leading to chronic, open-ended treatment. This approach is in contrast to older treatment approaches such as chemotherapy, which is often given for a limited duration followed by observation. When successful, chronic treatment with targeted agents can lead to unanticipated high costs. The following current cases at the VA San Diego Healthcare System illustrate this point:

• Renal cell carcinoma: 68-year-old man diagnosed in 2005 with a recurrence in 2012

- High-dose interleukin-2 (2 cycles); sunitinib (3.3 years); pazopanib (2 months); everolimus (2 months); sorafenib (3 months); axitinib (7 months)

• Cutaneous T-cell lymphoma: 68-year-old man started romidepsin September 22, 2010

The rate of FDA approval for oncology drugs has been accelerating rapidly in the past 15 years. Sequential therapies beyond second-line therapy are common as more agents become available. Table 2 shows FDA approval for all cancer drugs by decade.

As researchers continue to better understand the many pathways involved with the development and progression of cancer, they are beginning to combine multiple targeted agents to augment response rates, prolong survival, and reduce the potential for resistance. Recent combination regimens approved by the FDA include dabrafenib plus trametinib (January 2014), and ipilimumab plus nivolumab (October 2015), both for the treatment of melanoma. In November 2015, ixazomib was FDA approved to be used in combination with lenalidomide for multiple myeloma. Many more combination regimens are currently in clinical trials, and more combinations are expected to receive FDA approval. It is easy to see how the combination of multiple expensive agents with the prospect of prolonged therapy has the potential to increase the cost of many regimens to well over $100,000 per year.

Maintenance therapy is used to prolong PFS for patients receiving an excellent response to primary therapy. For example, VA costs for maintenance regimens include lenalidomide 10 mg daily: $8,314 for 28 days equals $216,177 for 2 years; bortezomib 1.3 mg/m² (2.6 mg) q: 2 weeks equals $60,730 for 2 years (includes waste as bortezomib 3.5-mg vials do not a contain preservative and must be discarded within 8 hours of preparation); and rituximab 800 mg q: 2 months equals $47,635 for 2 years.

Until recently, immunotherapy for cancer was limited to melanoma and renal cell carcinoma using interleukin-2 (aldesleukin) and interferon alfa. However, the immergence of new immunotherapies, such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have expanded the role of immunotherapy to many other, more common, malignancies, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, and many more.

Most randomized clinical trials study drugs as second- or occasionally third-line therapy. However, many patients continue to be treated beyond the third-line setting, often without evidence-based data to support potential benefit. Patients often place value on treatments unlikely to work so as not to give up hope. These “hopeful gambles,” even with the potential of significant toxicity and decreased quality of life (QOL), are common in cancer treatment.⁶ In addition, oncologists often overestimate the clinical benefit when considering additional therapy in this setting.⁷

Influx of New Patients

Outside the VHA setting, the financial burden of cancer treatment has led to an influx of new patients transferring care to the VHA to reduce out-of-pocket expenses. Because private insurance copays for oral agents are increasing, many reaching 20% to 30%, out-of-pocket expenses for medications can reach several thousand dollars per month. Patients often change insurance plans due to changing jobs or to decrease cost, or employers may change plans to save money, which may significantly alter or discontinue coverage. Patients often request that the VA provide medication while continuing to see only their private oncologist. This practice should be discouraged because the VA, without clinical involvement, may supply drugs for inappropriate indications. In addition, VA providers writing prescriptions for medications without personally following patients may be liable for poor outcomes.

VA PBM Services

Prior to 1995, the VA was a much criticized and poorly performing health care system that had experienced significant budget cuts, forcing many veterans to seek care outside the VA. Then beginning in 1995, a remarkable transformation occurred, which modernized and improved the VA into a system that consistently outperforms the private sector in quality of care, patient safety, patient satisfaction, all at a lower cost.⁸ The story of the VA’s transformation has been well chronicled by Phillip Longman.⁹

Under the direction of VA Under Secretary for Health Kenneth Kizer, MD, MPH, VA established PBM Clinical Services to develop and maintain the National Drug Formulary, create clinical guidance documents, and manage drug costs and utilization. A recent article by Heron and Geraci examined the functions and role of the VA PBM in controlling oncology drug costs.¹⁰ The following is a brief review of several documents and VA PBM responsibilities as reviewed by Heron and Geraci.

VA National Formulary

Prior to the establishment of the VA National Formulary in 1995, each VA maintained its own formulary, which led to extreme variability in drug access across the country. When a patient accessed care at different VAMCs, it was common for the patient’s medications to be changed based on the specific facility formulary. This practice led to many potential problems, such as lack of clinical benefit and potentially increased or new toxicities, and led to extra hospital visits for monitoring and adjustment of medications.

In contrast, the VA National Formulary now offers a uniform pharmacy benefit to all veterans by reducing variation in access to drugs. In addition, using preferred agents in each drug class provides VA with additional leverage when contracting with drug suppliers to reduce prices across the entire VA system.

Many oncology agents are not included on the VA National Formulary due to cost and the potential for off-label use. However, the formulary status of oncology agents in no way limits access or the availability of any oncology drug for appropriate patients. In fact, nonformulary approval requests work as a mechanism for review to ensure that these agents are used properly in the subset of patients who are most likely to benefit.

The PBM assesses all new oncology drugs for value and potential use within the VA, as well as cost impact. Following this assessment, various clinical guidance documents may be developed that are intended to guide clinicians in the proper use of medications for veterans. All documents prepared by the PBM undergo an extensive peer review by the Medical Advisory Panel and other experts in the field.

Drug Monographs

A drug monograph is a comprehensive, evidence-based drug review that summarizes efficacy and safety based on clinical trial data published in peer-reviewed journals, abstracts, and/or FDA Medical Review transcripts. Cost-effectiveness analysis is included if available.

Criteria for Use

Criteria for Use (CFU) are developed for drugs considered to be at high risk for inappropriate use or with safety concerns. The purpose of the CFU is to select patients most likely to benefit from these agents by using clinical criteria, which may qualify or eliminate a patient for treatment. National CFUs are available on the national PBM website. Local CFUs are often written and shared among oncology pharmacists via the VA oncology pharmacist listserv.

Abbreviated Reviews

Similar to drug monographs, abbreviated reviews are much shorter and focus on the relevant clinical sections of the drug monograph necessary for clinical or formulary decision making.

National Acquisition Center

The National Acquisition Center (NAC) is the pharmaceutical contracting mechanism for the VA and works closely with the PBM.⁵ The NAC pursues significant drug price reductions for the VA based on many strategies. Public Law 102-585 ensures that certain government agencies, including the VA, receive special discounts on pharmaceuticals, which is at least a 24% discount from the nonfederal Average Manufacturer Price. This is known as the Federal Supply Schedule (FSS) and/or Big 4 pricing. In addition, bulk purchases and performance-based incentive agreements can lead to substantial local discounts. By working with specific drug distribution and warehouse contractors, the NAC assures ready access to drugs for VA patients. The NAC also allows for an efficient drug inventory process, thus reducing inventory management costs.

Guidance Documents

In 2012, the VA Oncology Field Advisory Committee (FAC) created the High Cost Oncology Drug Work Group to address the impact of high-cost oncology drugs within the VA.¹¹ This work group was composed of VA oncologists and pharmacists whose efforts resulted in 5 guidance documents designed to reduce drug costs by optimizing therapy and reducing waste: (1) Dose Rounding in Oncology; (2) Oral Anticancer Drugs Dispensing and Monitoring; (3) Oncology Drug Table: Recommended Dispensing and Monitoring; (4) Chemotherapy Review Committee Process; and (5) Determining Clinical Benefit of High Cost Oncology Drugs. Reviews of 2 of these documents follows.

Determining Clinical Benefit of High Cost Oncology Drugs provides a decision tool to aid members of the oncology health care team in optimizing patient outcomes while attempting to obtain the greatest value from innovative therapies. When a high-cost or off-label request is made for a particular patient, using this process encourages thoughtful and evidence-based use of the drug by considering all clinical evidence in addition to the FDA-approved indication. Finally, a drug’s safety profile in relation to the indication, therapeutic goal, and specific patient characteristics and desires are integrated into a final decision to determine the appropriateness of the therapeutic intervention for the patient.

Oncology Drug Table: Recommended Dispensing and Monitoring contains a list of oral oncology drugs and includes recommendations for dispensing amount, adverse effects, laboratory monitoring, formulary status, approval requirements, and monthly cost of each agent based on the current NAC pricing.⁵ Cost awareness is critical when comparing alternative treatment options to minimize cost when treatments with similar benefits are considered. Most VA oncologists do not have easy access to the cost of various treatments and can be surprised about how expensive many common regimens cost. The costs listed in this document are updated about every 3 months.

Conclusion

Using newer, expensive targeted oncology agents in a cost-effective manner must be a proactive, collaborative, and multidisciplinary process. Pharmacists should not be solely responsible for monitoring and controlling high-cost treatments. Well-informed, evidence-based decisions are needed to ensure expensive agents are used in the subset of patients who are most likely to benefit. Clinical tools addressing value should be used to aid in appropriate and cost-effective treatment plans using drug monographs and CFUs, VHA Guidance on Determining Clinical Benefit of High Cost Oncology Drugs, and the Oral Chemotherapy Dispensing and Monitoring Reference, among other resources. Due to the subjective nature of value in medicine, agreeing on policy will have many challenges, such as how to place a value on various gains in overall survival, progression free survival, response rates, and QOL.

eAppendix

Updated January 20, 2016

The Million Veteran Program may play an important role in the recently announced cancer "moon shot." President Barack Obama and Vice President Joe Biden are promising to marshal federal and private resources to battle against cancer. Beginning with a bold announcement at the President’s State of the Union address, delivered January 12, and followed up by a slightly more detailed plan put forth by Biden a day later, the White House is focused on battling cancer by breaking down silos and increasing both public and private resources.

“The goal of this initiative — this ‘Moonshot’ — is to seize this moment,” Biden explained in a blog post. “To accelerate our efforts to progress towards a cure, and to unleash new discoveries and breakthroughs for other deadly diseases.”

Noting advances in immunotherapy, genomics and combined therapies, Biden argued that great strides have been made in cancer research, but the results are not necessarily reaching patients. “The science, data, and research results are trapped in silos, preventing faster progress and greater reach to patients,” Biden insisted. “It’s not just about developing game-changing treatments — it’s about delivering them to those who need them.”

Biden pledged that the federal government “will do everything it possibly can— through funding, targeted incentives, and increased private-sector coordination — to support research and enable progress.” Unclear, however, is whether the VA or the Murtha Cancer Center at Walter Reed National Military Medical Center will be involved in the effort. Later this month Biden will meet with cabinet secretaries and heads of relevant agencies to discuss ways to improve federal investment and support of cancer research and treatment.

VA Secretary Bob McDonald recently toured a Million Veteran Program (MVP) repository in Boston and touted the potential role in could play in the cancer moon shot, according to Military.com. Veterans who participate in the program donate blood for DNA extraction, which is linked to their health records. Created in 2012, MVP was expected to take 5 to 7 years to reach 1 million participants and already has registered more than 400,000 participants.

According to Politico, Biden has already made significant progress. The White House has a detailed plan leveraging the work of the National Institutes of Health (NIH) and private organizations that can compress 10 years of work into 5. The NIH is one of the few agencies that has received more funding from Congress in the latest budgets.

Medical and cancer organizations met the announcement with widespread approval. The American Association for Cancer Research (AACR) applauded the commitment to curing cancer. “We have indeed reached an inflection point, where the number of discoveries that are being made at such an accelerated pace are saving lives and bringing enormous hope for cancer patients, even those with advanced disease,” Dr. José Baselga, AACR president, said in a statement. “Now is the time for a major new initiative in cancer science that supports and builds upon our basic science foundation while translating these exciting scientific discoveries into improved treatments for cancer patients, such as in the areas of genomics, precision medicine, and immuno-oncology.”

“Vice President Biden’s call to leading cancer centers to break down silos and reach unprecedented levels of cooperation to enhance the effectiveness of cancer treatment, and for the oncology community to improve communication so that the care provided to patients at the world’s best cancer centers is available to everyone who needs it, echoes the work and mission of NCCN and our Member Institutions,” said Robert W. Carlson, MD, chief executive officer of the National Comprehensive Cancer Network (NCCN). “NCCN stands with President Obama, Vice President Biden, and their Administration on this crucial initiative, and we look forward to working to advance the goals of the initiative. It is time that people stop dying of cancer.”

The American Society of Clinical Oncology (ASCO) concurred. “With nearly 1.7 million people in the United States diagnosed with cancer each year, and the incidence of cancer expected to rise to 2.3 million cases per year by 2030, it is imperative that we do all we can to bring more effective treatments from the laboratory bench to the patient’s bedside as quickly as possible,”  Richard L. Schilsky, MD, ASCO chief medical officer, said in a statement. “We must recommit to vastly speeding the discovery of new cancer treatments and enabling the possibility of precision medicine for every individual with cancer.”

Updated January 20, 2016

The Million Veteran Program may play an important role in the recently announced cancer "moon shot." President Barack Obama and Vice President Joe Biden are promising to marshal federal and private resources to battle against cancer. Beginning with a bold announcement at the President’s State of the Union address, delivered January 12, and followed up by a slightly more detailed plan put forth by Biden a day later, the White House is focused on battling cancer by breaking down silos and increasing both public and private resources.

“The goal of this initiative — this ‘Moonshot’ — is to seize this moment,” Biden explained in a blog post. “To accelerate our efforts to progress towards a cure, and to unleash new discoveries and breakthroughs for other deadly diseases.”

Noting advances in immunotherapy, genomics and combined therapies, Biden argued that great strides have been made in cancer research, but the results are not necessarily reaching patients. “The science, data, and research results are trapped in silos, preventing faster progress and greater reach to patients,” Biden insisted. “It’s not just about developing game-changing treatments — it’s about delivering them to those who need them.”

Biden pledged that the federal government “will do everything it possibly can— through funding, targeted incentives, and increased private-sector coordination — to support research and enable progress.” Unclear, however, is whether the VA or the Murtha Cancer Center at Walter Reed National Military Medical Center will be involved in the effort. Later this month Biden will meet with cabinet secretaries and heads of relevant agencies to discuss ways to improve federal investment and support of cancer research and treatment.

VA Secretary Bob McDonald recently toured a Million Veteran Program (MVP) repository in Boston and touted the potential role in could play in the cancer moon shot, according to Military.com. Veterans who participate in the program donate blood for DNA extraction, which is linked to their health records. Created in 2012, MVP was expected to take 5 to 7 years to reach 1 million participants and already has registered more than 400,000 participants.

According to Politico, Biden has already made significant progress. The White House has a detailed plan leveraging the work of the National Institutes of Health (NIH) and private organizations that can compress 10 years of work into 5. The NIH is one of the few agencies that has received more funding from Congress in the latest budgets.

Medical and cancer organizations met the announcement with widespread approval. The American Association for Cancer Research (AACR) applauded the commitment to curing cancer. “We have indeed reached an inflection point, where the number of discoveries that are being made at such an accelerated pace are saving lives and bringing enormous hope for cancer patients, even those with advanced disease,” Dr. José Baselga, AACR president, said in a statement. “Now is the time for a major new initiative in cancer science that supports and builds upon our basic science foundation while translating these exciting scientific discoveries into improved treatments for cancer patients, such as in the areas of genomics, precision medicine, and immuno-oncology.”

“Vice President Biden’s call to leading cancer centers to break down silos and reach unprecedented levels of cooperation to enhance the effectiveness of cancer treatment, and for the oncology community to improve communication so that the care provided to patients at the world’s best cancer centers is available to everyone who needs it, echoes the work and mission of NCCN and our Member Institutions,” said Robert W. Carlson, MD, chief executive officer of the National Comprehensive Cancer Network (NCCN). “NCCN stands with President Obama, Vice President Biden, and their Administration on this crucial initiative, and we look forward to working to advance the goals of the initiative. It is time that people stop dying of cancer.”

The American Society of Clinical Oncology (ASCO) concurred. “With nearly 1.7 million people in the United States diagnosed with cancer each year, and the incidence of cancer expected to rise to 2.3 million cases per year by 2030, it is imperative that we do all we can to bring more effective treatments from the laboratory bench to the patient’s bedside as quickly as possible,”  Richard L. Schilsky, MD, ASCO chief medical officer, said in a statement. “We must recommit to vastly speeding the discovery of new cancer treatments and enabling the possibility of precision medicine for every individual with cancer.”

Updated January 20, 2016

The Million Veteran Program may play an important role in the recently announced cancer "moon shot." President Barack Obama and Vice President Joe Biden are promising to marshal federal and private resources to battle against cancer. Beginning with a bold announcement at the President’s State of the Union address, delivered January 12, and followed up by a slightly more detailed plan put forth by Biden a day later, the White House is focused on battling cancer by breaking down silos and increasing both public and private resources.

“The goal of this initiative — this ‘Moonshot’ — is to seize this moment,” Biden explained in a blog post. “To accelerate our efforts to progress towards a cure, and to unleash new discoveries and breakthroughs for other deadly diseases.”

Noting advances in immunotherapy, genomics and combined therapies, Biden argued that great strides have been made in cancer research, but the results are not necessarily reaching patients. “The science, data, and research results are trapped in silos, preventing faster progress and greater reach to patients,” Biden insisted. “It’s not just about developing game-changing treatments — it’s about delivering them to those who need them.”

Biden pledged that the federal government “will do everything it possibly can— through funding, targeted incentives, and increased private-sector coordination — to support research and enable progress.” Unclear, however, is whether the VA or the Murtha Cancer Center at Walter Reed National Military Medical Center will be involved in the effort. Later this month Biden will meet with cabinet secretaries and heads of relevant agencies to discuss ways to improve federal investment and support of cancer research and treatment.

VA Secretary Bob McDonald recently toured a Million Veteran Program (MVP) repository in Boston and touted the potential role in could play in the cancer moon shot, according to Military.com. Veterans who participate in the program donate blood for DNA extraction, which is linked to their health records. Created in 2012, MVP was expected to take 5 to 7 years to reach 1 million participants and already has registered more than 400,000 participants.

According to Politico, Biden has already made significant progress. The White House has a detailed plan leveraging the work of the National Institutes of Health (NIH) and private organizations that can compress 10 years of work into 5. The NIH is one of the few agencies that has received more funding from Congress in the latest budgets.

Medical and cancer organizations met the announcement with widespread approval. The American Association for Cancer Research (AACR) applauded the commitment to curing cancer. “We have indeed reached an inflection point, where the number of discoveries that are being made at such an accelerated pace are saving lives and bringing enormous hope for cancer patients, even those with advanced disease,” Dr. José Baselga, AACR president, said in a statement. “Now is the time for a major new initiative in cancer science that supports and builds upon our basic science foundation while translating these exciting scientific discoveries into improved treatments for cancer patients, such as in the areas of genomics, precision medicine, and immuno-oncology.”

“Vice President Biden’s call to leading cancer centers to break down silos and reach unprecedented levels of cooperation to enhance the effectiveness of cancer treatment, and for the oncology community to improve communication so that the care provided to patients at the world’s best cancer centers is available to everyone who needs it, echoes the work and mission of NCCN and our Member Institutions,” said Robert W. Carlson, MD, chief executive officer of the National Comprehensive Cancer Network (NCCN). “NCCN stands with President Obama, Vice President Biden, and their Administration on this crucial initiative, and we look forward to working to advance the goals of the initiative. It is time that people stop dying of cancer.”

The American Society of Clinical Oncology (ASCO) concurred. “With nearly 1.7 million people in the United States diagnosed with cancer each year, and the incidence of cancer expected to rise to 2.3 million cases per year by 2030, it is imperative that we do all we can to bring more effective treatments from the laboratory bench to the patient’s bedside as quickly as possible,”  Richard L. Schilsky, MD, ASCO chief medical officer, said in a statement. “We must recommit to vastly speeding the discovery of new cancer treatments and enabling the possibility of precision medicine for every individual with cancer.”

Vaccines are used to prevent bacterial infections, such as pneumonia, and viral diseases, such as influenza.¹ Recently, they are being used to prevent cancers. For example, the human papilloma virus vaccine prevents infection with the virus that is associated with cervical cancer.² Now there is another purpose for vaccines: They can be used therapeutically. Vaccines can be given even after a person manifests a tumor; they can cause the tumor to shrink or disappear. Therapeutic vaccines hold the potential to effect profound changes in the treatment of several cancers.

Biologics

Biologics, a recently developed class of weapons, can be but aren’t always relatively specific to cancer cells. Biologic agents include inhibitors and monoclonal antibodies. Inhibitors target specific functions, such as angiogenesis. However, inhibitors are not always selective for cancer cells. Angiogenesis inhibitors block formation of blood vessels. Like cytotoxic chemotherapy agents, they block the formation of blood vessels in normal cells as well as cancer cells. Cancer cells, however, generally grow more rapidly than do normal host cells, so they need more blood vessels faster to nourish their cells.³

Some inhibitors are more specific. An inhibitor molecule can be directed against a specific transcript that does not occur in normal cells. In normal cells, the breakpoint cluster region (BCR) gene on chromosome 22 directs synthesis of its protein product, whereas the abelson murine leukemia viral oncogene homolog 1 (ABL1) gene on chromosome 9 specifies another protein. However, in chronic myelogenous leukemia, the ends of those 2 chromosomes translocate, and the BCR/ABL1 transcript is a hybrid of RNA derived from the original chromosome and that of the newly attached, translocated chromosome 9. This hybrid RNA directs synthesis of a fusion protein, a tyrosine kinase; the fusion protein is not produced in normal host cells. Thus imatinib, an inhibitor directed at the fusion protein, inhibits the cancer cells specifically.⁴

Monoclonal Antibodies

Monoclonal antibodies exploit the host’s immune system to destroy cancer cells. Like the inhibitors, monoclonal antibodies can be directed against a specific functional protein, which is not necessarily specific to tumor cells, or against a protein or family of proteins unique to the cancer cells. For example, trastuzumab is a monoclonal antibody directed against the HER2/neu oncogene, which is amplified in some breast cancers.⁵ The host’s immune system recognizes the antibodyantigen complex and signals its macrophages to destroy the complex, and the cancer cell dies.

Vaccines also exploit the immune system. One way to immunize against a virus, is to introduce a live or killed virus or a part of a virus—usually a part of a viral protein—into the recipient. The immune system recognizes the foreign virus and makes antibodies. When the immune system is challenged by exposure to the pathogenic virus, the antiviral antibodies recognize and bind to it. The host’s macrophages then engulf the antigenantibody complex and destroy it.⁶ This type of vaccine prevents infection.

Viral Vaccines

Few vaccines prevent specific cancers. Immunization against the hepatitis B virus, for example, confers immunity to a virus whose infection is a major risk factor for hepatocellular carcinoma.⁷ Thus it is not truly an anticancer vaccine but rather an antiviral vaccine. Similarly, the HPV
vaccine does not prevent cervical cancer but confers immunity
to a virus that causes cervical cancer.²

Using vaccines to prevent cancer in general is now becoming feasible. Cancer vaccines in use or in development at this time are of 2 general types: those derived from a single tumor and are designed to elicit immunity to that particular tumor in that particular individual host; and those designed to provoke an immune response to that particular type of tumor in any host. The latter type can be mass produced, whereas vaccines of the first type are restricted to the host of origin.

Autologous Vaccines

At the time of biopsy or surgical excision, tumors are mechanically and enzymatically dissociated into single cells, then grown in tissue culture. When they are cultured in suspension with agitation, the cancer stem cells (CSCs) form spheroids, and other cell types do not. The CSCs are the progenitor cells of the specific tumor, much like bone marrow stem cells are the progenitors of the myeloid, erythroid, and megakaryocyte (platelet) cell lineages of human blood. After the CSCs are expanded, the spheroids are harvested, and their RNA is extracted. The messenger RNAs, which specify the proteins made by the CSCs, are converted to complementary DNAs, which are then amplified using the polymerase chain reaction.⁸

Meanwhile, the patient’s peripheral blood mononuclear cells (PBMCs) are harvested from the blood by leukapheresis. The PBMCs are then enriched for monocytes by immunologic depletion of B and T cells. The monocytes are cultured in the presence of interleukin-4 and granulocytemacrophage-colony-stimulating factor (GM-CSF), and they become immature dendritic cells after 5 days. These immature dendritic cells are transfected with the amplified DNA from the CSC tumor spheres and grown for 2 more days in a medium supplemented with interleukin-1b (IL-1b), interleukin-6 (IL-6), tumor necrosis factor-α, and prostaglandin E2, then tested for markers characteristic of dendritic cells and frozen.

Aliquots of these transfected dendritic cells are injected into the patient at intervals over several months. Dendritic cells, which are the most efficient cells at eliciting an immune response, present the tumor CSC antigens to the patient’s immune system, which develops antibodies to the antigens presented on the dendritic cells and proceeds to destroy the tumor CSCs remaining in the patient’s tumor. Without its CSCs, the tumor is unable to revitalize itself, the rest of the tumor cells eventually die, and the tumor shrinks. The patient is monitored for immune response, and the tumor is regularly imaged. This vaccine is an example of therapeutic use: It can cause tumor regression.⁸

Sipuleucil-T is another example of an autologous vaccine used for therapeutic purposes. The patient’s antigenpresenting cells (APCs) are harvested by leukopheresis. They are then cultured in the presence of the protein made by fusing prostatic antigen phosphatase (PAP) with the GM-CSF to form the fusion protein PAP-GM-CSF. These modified APCs are then reinjected into the same host. Sipuleucil-T is now FDA approved for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) and has been shown to extend life by approximately 4 months.⁹

Universal Vaccine for a Specific Tumor

Cancer vaccines can also be prepared in a more conventional manner, analogous to the more commonly used vaccines, and given to all patients with that specific tumor. PROSTVAC is another vaccine for mCRPC as well as for earlier-stage prostate cancer. The DNA specifying prostate-specific antigen (PSA), the secreted protein expressed by the tumor, is mutated very slightly and inserted into a vaccinia virus (Figure). Also inserted into the vaccinia virus are DNAs encoding 3 proteins that
stimulate the patient’s immune system: B7.1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte functionassociated antigen-3 (LFA-3).

This recombinant viral vector is propagated in tissue culture, purified, and administered to the patient subcutaneously. The virus replicates for a short period in the host, expressing the 3 immunostimulatory molecules and the mutated PSA molecule protein product, which differs by 1 amino acid from that expressed by the patient’s tumor. The vaccinia virus and the mutant protein are recognized as foreign by the patient’s immune system, whereas the 3 immunostimulatory molecules are not, as they are the same as the host’s immunostimulatory molecules.

Subsequent boosts, administered over about 5 months, are with a fowlpox virus vector (which does not replicate in the patient) containing the same 4 genes that had been inserted into the vaccinia virus. This strategy enhances the immune response to the mutant tumor product and ensures that the host is not generating a response to the vaccinia virus. The mutant tumor product is sufficiently similar to the patient’s native tumor product that the immune system mounts a response to both proteins. The T cells generated in response to the mutant protein bind to both PSA and mutated PSA molecule proteins, and cells harboring these proteins are destroyed.¹⁰

Whereas the T-cell response is important for the activity of the PROSTVAC vaccine, and there is no evidence for formation of anti-PSA antibodies, other vaccines exploit both B- and T-cell responses.^10,11 After a virus commandeers the host cell’s replication, transcription, and translation machinery, the macrophage breaks down the viral protein product (the mutated or immunogenic molecule) into small fragments. These fragments bind to major histocompatibility complex (MHC) class II molecules, which are produced by the macrophages. These complexes of antigen (virus) fragments with MHC class II molecules are transported to the surface of the macrophage, where the antigen is presented to lymphocytes. A receptor on a B lymphocyte adheres to the viral antigen and thus becomes an activated B cell, which divides and produces many copies. The B lymphocytes mature into plasma cells and release antibodies that adhere to the virus. A helper T-cell receptor can adhere to the antigen-MHC class II complex displayed on the B cell and activate the lymphocyte, causing the release of more and different cytokines. The cytokines stimulate the activated B cell to divide, producing functionally mature antibodies that recognize and attach to the virus. Macrophages can then engulf and destroy the virus, or the antibody-linked viruses can be excreted in the urine or stool.¹²

When viruses (eg, the recombinant vaccinia virus of the PROSTVAC vaccine) infect cells and replicate, fragments of viral proteins become attached to MHC class I molecules (see Box). These complexes attach to the cell surface and are presented to cytotoxic T cells. The activated cytotoxic T cells divide and destroy cells harboring the virus or viral antigens.¹²

Some of the B lymphocytes become memory B cells. Similarly, some of the T lymphocytes become memory T cells. These memory B cells respond and replicate rapidly on re-exposure to the virus or viral proteins to produce antigen-specific antibodies.¹²

When a macrophage engulfs and breaks down a tumor cell harboring a PSA molecule, other tumor-specific protein fragments are released. These tumor-specific fragments then serve as antigens and elicit an immune response, generating even more antitumor antibodies and T-cell interactions. Thus the tumor regresses. Importantly, this type of vaccine can be mass produced.

Vaccines With Chemotherapy

Another approach to the design of a tumor-specific vaccine is based on tumor-associated peptides (TUMAPs). These TUMAPs are highly overexpressed in tumors relative to a number of normal, healthy tissues. Nine highly immunogenic TUMAPs from 80 specimens of the same tumor type, identified by mass spectrometry, gene expression profiling, literature-based functional assessment, bioinformatics, and human T-cell assays, are used to prepare IMA901, a multipeptide vaccine against the specific tumor, renal cell carcinoma. The pool of selected peptides, composed of 9 to 16 amino acids, is then administered to patients following a dose of the immunomodulator GM-CSF for a total of as many as 17 injections. Low-dose cyclophosphamide administered prior to the first vaccination downregulates regulator T cells, enhancing immune response and resulting in prolonged survival.¹³ This type of vaccine can also be mass produced.

Conclusions

The vaccines that are currently in use or in clinical trials are being used in patients with advanced disease. As such, they are therapeutic rather than prophylactic. It is inevitable that more vaccines will earn FDA approval. Eventually, they will be used in earlier-stage disease. It is conceivable that some can be used prophylactically when a malignancy first becomes detectable, especially as more sensitive detection methods are developed. Vaccine delivery systems are likely to change as researchers investigate and adopt matrix materials that increase efficacy.

Cancer vaccines hold the potential for greater selectivity in treatment of malignancies. These vaccines may enable us to use cytotoxic chemotherapy agents less often or perhaps more effectively when used in conjunction with vaccines. Vaccines that can be mass produced could conceivably decrease the financial burden of cancer treatment as well as the human cost of malignant diseases and their therapy and care requirements.

Solid-tumor and hematologic malignancy vaccines are coming into wider use as the science is better understood and more methods of generating immune responses are explored. A personalized cancer vaccine, sipuleucel-T, is FDA approved for clinical use against mCRPC.9 A poxvirus-based vaccine, PROSTVAC, also against mCRPC, is in phase 3 clinical trials.^10,11 The multipeptide renal cell carcinoma vaccine IMA901 is also in phase 3 clinical trials.¹³ A personalized vaccine against glioblastoma multiforme CSCs has extended progression-free survival in its initial pretrial study.^8,14 Additional glioblastoma, melanoma, and other vaccines are in clinical trials and under development.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

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Vaccines are used to prevent bacterial infections, such as pneumonia, and viral diseases, such as influenza.¹ Recently, they are being used to prevent cancers. For example, the human papilloma virus vaccine prevents infection with the virus that is associated with cervical cancer.² Now there is another purpose for vaccines: They can be used therapeutically. Vaccines can be given even after a person manifests a tumor; they can cause the tumor to shrink or disappear. Therapeutic vaccines hold the potential to effect profound changes in the treatment of several cancers.

Biologics

Biologics, a recently developed class of weapons, can be but aren’t always relatively specific to cancer cells. Biologic agents include inhibitors and monoclonal antibodies. Inhibitors target specific functions, such as angiogenesis. However, inhibitors are not always selective for cancer cells. Angiogenesis inhibitors block formation of blood vessels. Like cytotoxic chemotherapy agents, they block the formation of blood vessels in normal cells as well as cancer cells. Cancer cells, however, generally grow more rapidly than do normal host cells, so they need more blood vessels faster to nourish their cells.³

Some inhibitors are more specific. An inhibitor molecule can be directed against a specific transcript that does not occur in normal cells. In normal cells, the breakpoint cluster region (BCR) gene on chromosome 22 directs synthesis of its protein product, whereas the abelson murine leukemia viral oncogene homolog 1 (ABL1) gene on chromosome 9 specifies another protein. However, in chronic myelogenous leukemia, the ends of those 2 chromosomes translocate, and the BCR/ABL1 transcript is a hybrid of RNA derived from the original chromosome and that of the newly attached, translocated chromosome 9. This hybrid RNA directs synthesis of a fusion protein, a tyrosine kinase; the fusion protein is not produced in normal host cells. Thus imatinib, an inhibitor directed at the fusion protein, inhibits the cancer cells specifically.⁴

Monoclonal Antibodies

Monoclonal antibodies exploit the host’s immune system to destroy cancer cells. Like the inhibitors, monoclonal antibodies can be directed against a specific functional protein, which is not necessarily specific to tumor cells, or against a protein or family of proteins unique to the cancer cells. For example, trastuzumab is a monoclonal antibody directed against the HER2/neu oncogene, which is amplified in some breast cancers.⁵ The host’s immune system recognizes the antibodyantigen complex and signals its macrophages to destroy the complex, and the cancer cell dies.

Vaccines also exploit the immune system. One way to immunize against a virus, is to introduce a live or killed virus or a part of a virus—usually a part of a viral protein—into the recipient. The immune system recognizes the foreign virus and makes antibodies. When the immune system is challenged by exposure to the pathogenic virus, the antiviral antibodies recognize and bind to it. The host’s macrophages then engulf the antigenantibody complex and destroy it.⁶ This type of vaccine prevents infection.

Viral Vaccines

Few vaccines prevent specific cancers. Immunization against the hepatitis B virus, for example, confers immunity to a virus whose infection is a major risk factor for hepatocellular carcinoma.⁷ Thus it is not truly an anticancer vaccine but rather an antiviral vaccine. Similarly, the HPV
vaccine does not prevent cervical cancer but confers immunity
to a virus that causes cervical cancer.²

Using vaccines to prevent cancer in general is now becoming feasible. Cancer vaccines in use or in development at this time are of 2 general types: those derived from a single tumor and are designed to elicit immunity to that particular tumor in that particular individual host; and those designed to provoke an immune response to that particular type of tumor in any host. The latter type can be mass produced, whereas vaccines of the first type are restricted to the host of origin.

Autologous Vaccines

At the time of biopsy or surgical excision, tumors are mechanically and enzymatically dissociated into single cells, then grown in tissue culture. When they are cultured in suspension with agitation, the cancer stem cells (CSCs) form spheroids, and other cell types do not. The CSCs are the progenitor cells of the specific tumor, much like bone marrow stem cells are the progenitors of the myeloid, erythroid, and megakaryocyte (platelet) cell lineages of human blood. After the CSCs are expanded, the spheroids are harvested, and their RNA is extracted. The messenger RNAs, which specify the proteins made by the CSCs, are converted to complementary DNAs, which are then amplified using the polymerase chain reaction.⁸

Meanwhile, the patient’s peripheral blood mononuclear cells (PBMCs) are harvested from the blood by leukapheresis. The PBMCs are then enriched for monocytes by immunologic depletion of B and T cells. The monocytes are cultured in the presence of interleukin-4 and granulocytemacrophage-colony-stimulating factor (GM-CSF), and they become immature dendritic cells after 5 days. These immature dendritic cells are transfected with the amplified DNA from the CSC tumor spheres and grown for 2 more days in a medium supplemented with interleukin-1b (IL-1b), interleukin-6 (IL-6), tumor necrosis factor-α, and prostaglandin E2, then tested for markers characteristic of dendritic cells and frozen.

Aliquots of these transfected dendritic cells are injected into the patient at intervals over several months. Dendritic cells, which are the most efficient cells at eliciting an immune response, present the tumor CSC antigens to the patient’s immune system, which develops antibodies to the antigens presented on the dendritic cells and proceeds to destroy the tumor CSCs remaining in the patient’s tumor. Without its CSCs, the tumor is unable to revitalize itself, the rest of the tumor cells eventually die, and the tumor shrinks. The patient is monitored for immune response, and the tumor is regularly imaged. This vaccine is an example of therapeutic use: It can cause tumor regression.⁸

Sipuleucil-T is another example of an autologous vaccine used for therapeutic purposes. The patient’s antigenpresenting cells (APCs) are harvested by leukopheresis. They are then cultured in the presence of the protein made by fusing prostatic antigen phosphatase (PAP) with the GM-CSF to form the fusion protein PAP-GM-CSF. These modified APCs are then reinjected into the same host. Sipuleucil-T is now FDA approved for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) and has been shown to extend life by approximately 4 months.⁹

Universal Vaccine for a Specific Tumor

Cancer vaccines can also be prepared in a more conventional manner, analogous to the more commonly used vaccines, and given to all patients with that specific tumor. PROSTVAC is another vaccine for mCRPC as well as for earlier-stage prostate cancer. The DNA specifying prostate-specific antigen (PSA), the secreted protein expressed by the tumor, is mutated very slightly and inserted into a vaccinia virus (Figure). Also inserted into the vaccinia virus are DNAs encoding 3 proteins that
stimulate the patient’s immune system: B7.1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte functionassociated antigen-3 (LFA-3).

This recombinant viral vector is propagated in tissue culture, purified, and administered to the patient subcutaneously. The virus replicates for a short period in the host, expressing the 3 immunostimulatory molecules and the mutated PSA molecule protein product, which differs by 1 amino acid from that expressed by the patient’s tumor. The vaccinia virus and the mutant protein are recognized as foreign by the patient’s immune system, whereas the 3 immunostimulatory molecules are not, as they are the same as the host’s immunostimulatory molecules.

Subsequent boosts, administered over about 5 months, are with a fowlpox virus vector (which does not replicate in the patient) containing the same 4 genes that had been inserted into the vaccinia virus. This strategy enhances the immune response to the mutant tumor product and ensures that the host is not generating a response to the vaccinia virus. The mutant tumor product is sufficiently similar to the patient’s native tumor product that the immune system mounts a response to both proteins. The T cells generated in response to the mutant protein bind to both PSA and mutated PSA molecule proteins, and cells harboring these proteins are destroyed.¹⁰

Whereas the T-cell response is important for the activity of the PROSTVAC vaccine, and there is no evidence for formation of anti-PSA antibodies, other vaccines exploit both B- and T-cell responses.^10,11 After a virus commandeers the host cell’s replication, transcription, and translation machinery, the macrophage breaks down the viral protein product (the mutated or immunogenic molecule) into small fragments. These fragments bind to major histocompatibility complex (MHC) class II molecules, which are produced by the macrophages. These complexes of antigen (virus) fragments with MHC class II molecules are transported to the surface of the macrophage, where the antigen is presented to lymphocytes. A receptor on a B lymphocyte adheres to the viral antigen and thus becomes an activated B cell, which divides and produces many copies. The B lymphocytes mature into plasma cells and release antibodies that adhere to the virus. A helper T-cell receptor can adhere to the antigen-MHC class II complex displayed on the B cell and activate the lymphocyte, causing the release of more and different cytokines. The cytokines stimulate the activated B cell to divide, producing functionally mature antibodies that recognize and attach to the virus. Macrophages can then engulf and destroy the virus, or the antibody-linked viruses can be excreted in the urine or stool.¹²

When viruses (eg, the recombinant vaccinia virus of the PROSTVAC vaccine) infect cells and replicate, fragments of viral proteins become attached to MHC class I molecules (see Box). These complexes attach to the cell surface and are presented to cytotoxic T cells. The activated cytotoxic T cells divide and destroy cells harboring the virus or viral antigens.¹²

Some of the B lymphocytes become memory B cells. Similarly, some of the T lymphocytes become memory T cells. These memory B cells respond and replicate rapidly on re-exposure to the virus or viral proteins to produce antigen-specific antibodies.¹²

When a macrophage engulfs and breaks down a tumor cell harboring a PSA molecule, other tumor-specific protein fragments are released. These tumor-specific fragments then serve as antigens and elicit an immune response, generating even more antitumor antibodies and T-cell interactions. Thus the tumor regresses. Importantly, this type of vaccine can be mass produced.

Vaccines With Chemotherapy

Another approach to the design of a tumor-specific vaccine is based on tumor-associated peptides (TUMAPs). These TUMAPs are highly overexpressed in tumors relative to a number of normal, healthy tissues. Nine highly immunogenic TUMAPs from 80 specimens of the same tumor type, identified by mass spectrometry, gene expression profiling, literature-based functional assessment, bioinformatics, and human T-cell assays, are used to prepare IMA901, a multipeptide vaccine against the specific tumor, renal cell carcinoma. The pool of selected peptides, composed of 9 to 16 amino acids, is then administered to patients following a dose of the immunomodulator GM-CSF for a total of as many as 17 injections. Low-dose cyclophosphamide administered prior to the first vaccination downregulates regulator T cells, enhancing immune response and resulting in prolonged survival.¹³ This type of vaccine can also be mass produced.

Conclusions

The vaccines that are currently in use or in clinical trials are being used in patients with advanced disease. As such, they are therapeutic rather than prophylactic. It is inevitable that more vaccines will earn FDA approval. Eventually, they will be used in earlier-stage disease. It is conceivable that some can be used prophylactically when a malignancy first becomes detectable, especially as more sensitive detection methods are developed. Vaccine delivery systems are likely to change as researchers investigate and adopt matrix materials that increase efficacy.

Cancer vaccines hold the potential for greater selectivity in treatment of malignancies. These vaccines may enable us to use cytotoxic chemotherapy agents less often or perhaps more effectively when used in conjunction with vaccines. Vaccines that can be mass produced could conceivably decrease the financial burden of cancer treatment as well as the human cost of malignant diseases and their therapy and care requirements.

Solid-tumor and hematologic malignancy vaccines are coming into wider use as the science is better understood and more methods of generating immune responses are explored. A personalized cancer vaccine, sipuleucel-T, is FDA approved for clinical use against mCRPC.9 A poxvirus-based vaccine, PROSTVAC, also against mCRPC, is in phase 3 clinical trials.^10,11 The multipeptide renal cell carcinoma vaccine IMA901 is also in phase 3 clinical trials.¹³ A personalized vaccine against glioblastoma multiforme CSCs has extended progression-free survival in its initial pretrial study.^8,14 Additional glioblastoma, melanoma, and other vaccines are in clinical trials and under development.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to continue reading.

Vaccines are used to prevent bacterial infections, such as pneumonia, and viral diseases, such as influenza.¹ Recently, they are being used to prevent cancers. For example, the human papilloma virus vaccine prevents infection with the virus that is associated with cervical cancer.² Now there is another purpose for vaccines: They can be used therapeutically. Vaccines can be given even after a person manifests a tumor; they can cause the tumor to shrink or disappear. Therapeutic vaccines hold the potential to effect profound changes in the treatment of several cancers.

Biologics

Biologics, a recently developed class of weapons, can be but aren’t always relatively specific to cancer cells. Biologic agents include inhibitors and monoclonal antibodies. Inhibitors target specific functions, such as angiogenesis. However, inhibitors are not always selective for cancer cells. Angiogenesis inhibitors block formation of blood vessels. Like cytotoxic chemotherapy agents, they block the formation of blood vessels in normal cells as well as cancer cells. Cancer cells, however, generally grow more rapidly than do normal host cells, so they need more blood vessels faster to nourish their cells.³

Some inhibitors are more specific. An inhibitor molecule can be directed against a specific transcript that does not occur in normal cells. In normal cells, the breakpoint cluster region (BCR) gene on chromosome 22 directs synthesis of its protein product, whereas the abelson murine leukemia viral oncogene homolog 1 (ABL1) gene on chromosome 9 specifies another protein. However, in chronic myelogenous leukemia, the ends of those 2 chromosomes translocate, and the BCR/ABL1 transcript is a hybrid of RNA derived from the original chromosome and that of the newly attached, translocated chromosome 9. This hybrid RNA directs synthesis of a fusion protein, a tyrosine kinase; the fusion protein is not produced in normal host cells. Thus imatinib, an inhibitor directed at the fusion protein, inhibits the cancer cells specifically.⁴

Monoclonal Antibodies

Monoclonal antibodies exploit the host’s immune system to destroy cancer cells. Like the inhibitors, monoclonal antibodies can be directed against a specific functional protein, which is not necessarily specific to tumor cells, or against a protein or family of proteins unique to the cancer cells. For example, trastuzumab is a monoclonal antibody directed against the HER2/neu oncogene, which is amplified in some breast cancers.⁵ The host’s immune system recognizes the antibodyantigen complex and signals its macrophages to destroy the complex, and the cancer cell dies.

Vaccines also exploit the immune system. One way to immunize against a virus, is to introduce a live or killed virus or a part of a virus—usually a part of a viral protein—into the recipient. The immune system recognizes the foreign virus and makes antibodies. When the immune system is challenged by exposure to the pathogenic virus, the antiviral antibodies recognize and bind to it. The host’s macrophages then engulf the antigenantibody complex and destroy it.⁶ This type of vaccine prevents infection.

Viral Vaccines

Few vaccines prevent specific cancers. Immunization against the hepatitis B virus, for example, confers immunity to a virus whose infection is a major risk factor for hepatocellular carcinoma.⁷ Thus it is not truly an anticancer vaccine but rather an antiviral vaccine. Similarly, the HPV
vaccine does not prevent cervical cancer but confers immunity
to a virus that causes cervical cancer.²

Using vaccines to prevent cancer in general is now becoming feasible. Cancer vaccines in use or in development at this time are of 2 general types: those derived from a single tumor and are designed to elicit immunity to that particular tumor in that particular individual host; and those designed to provoke an immune response to that particular type of tumor in any host. The latter type can be mass produced, whereas vaccines of the first type are restricted to the host of origin.

Autologous Vaccines

At the time of biopsy or surgical excision, tumors are mechanically and enzymatically dissociated into single cells, then grown in tissue culture. When they are cultured in suspension with agitation, the cancer stem cells (CSCs) form spheroids, and other cell types do not. The CSCs are the progenitor cells of the specific tumor, much like bone marrow stem cells are the progenitors of the myeloid, erythroid, and megakaryocyte (platelet) cell lineages of human blood. After the CSCs are expanded, the spheroids are harvested, and their RNA is extracted. The messenger RNAs, which specify the proteins made by the CSCs, are converted to complementary DNAs, which are then amplified using the polymerase chain reaction.⁸

Meanwhile, the patient’s peripheral blood mononuclear cells (PBMCs) are harvested from the blood by leukapheresis. The PBMCs are then enriched for monocytes by immunologic depletion of B and T cells. The monocytes are cultured in the presence of interleukin-4 and granulocytemacrophage-colony-stimulating factor (GM-CSF), and they become immature dendritic cells after 5 days. These immature dendritic cells are transfected with the amplified DNA from the CSC tumor spheres and grown for 2 more days in a medium supplemented with interleukin-1b (IL-1b), interleukin-6 (IL-6), tumor necrosis factor-α, and prostaglandin E2, then tested for markers characteristic of dendritic cells and frozen.

Aliquots of these transfected dendritic cells are injected into the patient at intervals over several months. Dendritic cells, which are the most efficient cells at eliciting an immune response, present the tumor CSC antigens to the patient’s immune system, which develops antibodies to the antigens presented on the dendritic cells and proceeds to destroy the tumor CSCs remaining in the patient’s tumor. Without its CSCs, the tumor is unable to revitalize itself, the rest of the tumor cells eventually die, and the tumor shrinks. The patient is monitored for immune response, and the tumor is regularly imaged. This vaccine is an example of therapeutic use: It can cause tumor regression.⁸

Sipuleucil-T is another example of an autologous vaccine used for therapeutic purposes. The patient’s antigenpresenting cells (APCs) are harvested by leukopheresis. They are then cultured in the presence of the protein made by fusing prostatic antigen phosphatase (PAP) with the GM-CSF to form the fusion protein PAP-GM-CSF. These modified APCs are then reinjected into the same host. Sipuleucil-T is now FDA approved for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) and has been shown to extend life by approximately 4 months.⁹

Universal Vaccine for a Specific Tumor

Cancer vaccines can also be prepared in a more conventional manner, analogous to the more commonly used vaccines, and given to all patients with that specific tumor. PROSTVAC is another vaccine for mCRPC as well as for earlier-stage prostate cancer. The DNA specifying prostate-specific antigen (PSA), the secreted protein expressed by the tumor, is mutated very slightly and inserted into a vaccinia virus (Figure). Also inserted into the vaccinia virus are DNAs encoding 3 proteins that
stimulate the patient’s immune system: B7.1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte functionassociated antigen-3 (LFA-3).

This recombinant viral vector is propagated in tissue culture, purified, and administered to the patient subcutaneously. The virus replicates for a short period in the host, expressing the 3 immunostimulatory molecules and the mutated PSA molecule protein product, which differs by 1 amino acid from that expressed by the patient’s tumor. The vaccinia virus and the mutant protein are recognized as foreign by the patient’s immune system, whereas the 3 immunostimulatory molecules are not, as they are the same as the host’s immunostimulatory molecules.

Subsequent boosts, administered over about 5 months, are with a fowlpox virus vector (which does not replicate in the patient) containing the same 4 genes that had been inserted into the vaccinia virus. This strategy enhances the immune response to the mutant tumor product and ensures that the host is not generating a response to the vaccinia virus. The mutant tumor product is sufficiently similar to the patient’s native tumor product that the immune system mounts a response to both proteins. The T cells generated in response to the mutant protein bind to both PSA and mutated PSA molecule proteins, and cells harboring these proteins are destroyed.¹⁰

Whereas the T-cell response is important for the activity of the PROSTVAC vaccine, and there is no evidence for formation of anti-PSA antibodies, other vaccines exploit both B- and T-cell responses.^10,11 After a virus commandeers the host cell’s replication, transcription, and translation machinery, the macrophage breaks down the viral protein product (the mutated or immunogenic molecule) into small fragments. These fragments bind to major histocompatibility complex (MHC) class II molecules, which are produced by the macrophages. These complexes of antigen (virus) fragments with MHC class II molecules are transported to the surface of the macrophage, where the antigen is presented to lymphocytes. A receptor on a B lymphocyte adheres to the viral antigen and thus becomes an activated B cell, which divides and produces many copies. The B lymphocytes mature into plasma cells and release antibodies that adhere to the virus. A helper T-cell receptor can adhere to the antigen-MHC class II complex displayed on the B cell and activate the lymphocyte, causing the release of more and different cytokines. The cytokines stimulate the activated B cell to divide, producing functionally mature antibodies that recognize and attach to the virus. Macrophages can then engulf and destroy the virus, or the antibody-linked viruses can be excreted in the urine or stool.¹²

When viruses (eg, the recombinant vaccinia virus of the PROSTVAC vaccine) infect cells and replicate, fragments of viral proteins become attached to MHC class I molecules (see Box). These complexes attach to the cell surface and are presented to cytotoxic T cells. The activated cytotoxic T cells divide and destroy cells harboring the virus or viral antigens.¹²

Some of the B lymphocytes become memory B cells. Similarly, some of the T lymphocytes become memory T cells. These memory B cells respond and replicate rapidly on re-exposure to the virus or viral proteins to produce antigen-specific antibodies.¹²

When a macrophage engulfs and breaks down a tumor cell harboring a PSA molecule, other tumor-specific protein fragments are released. These tumor-specific fragments then serve as antigens and elicit an immune response, generating even more antitumor antibodies and T-cell interactions. Thus the tumor regresses. Importantly, this type of vaccine can be mass produced.

Vaccines With Chemotherapy

Another approach to the design of a tumor-specific vaccine is based on tumor-associated peptides (TUMAPs). These TUMAPs are highly overexpressed in tumors relative to a number of normal, healthy tissues. Nine highly immunogenic TUMAPs from 80 specimens of the same tumor type, identified by mass spectrometry, gene expression profiling, literature-based functional assessment, bioinformatics, and human T-cell assays, are used to prepare IMA901, a multipeptide vaccine against the specific tumor, renal cell carcinoma. The pool of selected peptides, composed of 9 to 16 amino acids, is then administered to patients following a dose of the immunomodulator GM-CSF for a total of as many as 17 injections. Low-dose cyclophosphamide administered prior to the first vaccination downregulates regulator T cells, enhancing immune response and resulting in prolonged survival.¹³ This type of vaccine can also be mass produced.

Conclusions

The vaccines that are currently in use or in clinical trials are being used in patients with advanced disease. As such, they are therapeutic rather than prophylactic. It is inevitable that more vaccines will earn FDA approval. Eventually, they will be used in earlier-stage disease. It is conceivable that some can be used prophylactically when a malignancy first becomes detectable, especially as more sensitive detection methods are developed. Vaccine delivery systems are likely to change as researchers investigate and adopt matrix materials that increase efficacy.

Cancer vaccines hold the potential for greater selectivity in treatment of malignancies. These vaccines may enable us to use cytotoxic chemotherapy agents less often or perhaps more effectively when used in conjunction with vaccines. Vaccines that can be mass produced could conceivably decrease the financial burden of cancer treatment as well as the human cost of malignant diseases and their therapy and care requirements.

Solid-tumor and hematologic malignancy vaccines are coming into wider use as the science is better understood and more methods of generating immune responses are explored. A personalized cancer vaccine, sipuleucel-T, is FDA approved for clinical use against mCRPC.9 A poxvirus-based vaccine, PROSTVAC, also against mCRPC, is in phase 3 clinical trials.^10,11 The multipeptide renal cell carcinoma vaccine IMA901 is also in phase 3 clinical trials.¹³ A personalized vaccine against glioblastoma multiforme CSCs has extended progression-free survival in its initial pretrial study.^8,14 Additional glioblastoma, melanoma, and other vaccines are in clinical trials and under development.

Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Click here to continue reading.

Patients with advanced melanoma who were treated with immunotherapy responded better if they harbored mutations in the NRAS gene, according to a study published March 3 in Cancer Immunology Research.

Out of 229 cases retrospectively analyzed, 26% had mutations in NRAS^G12/G13/Q61, 23% had BRAF^V600, and 51% were wild type for NRAS and BRAF. Patients received first-line therapy with high-dose IL-2 (25%), ipilimumab (62%), or anti-PD-1/PD-L1 (12%), investigators reported (Cancer Immunol. Res. 2015 March 3).

©benjaminalbiach/ThinkStock

Complete or partial responses were found in 32% of patients with NRAS-mutant melanomas, compared with 20% of those without NRAS mutations (P = .07). Clinical benefit (defined as complete response, partial response, or stable disease for 24 weeks or longer) was observed in 50% of the NRAS mutant group vs. 30% of the non–mutant NRAS group (P < .01), reported Dr. Douglas B. Johnson of Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and associates.

Although the numbers for individual agents were small, the NRAS-mutant benefit was most pronounced for immune checkpoint inhibitors, especially anti-PD-1/PD-L1 therapy, where clinical benefit was observed in 8 of 11 NRAS-mutant patients vs. 13 of 37 patients with wild-type NRAS.

“This finding could have implications for molecular testing and treatment decision making, and it provides early insights into the complex relationship between tumor genetics and the immune response,” Dr. Johnson and associates wrote.

Patients with NRAS-mutant melanoma account for 15%-20% of all melanomas, and the mutation is associated with a poorer prognosis. The authors speculate that elevated PD-1 expression may be a factor in inferior prognosis of NRAS-mutant phenotypes as well as the observed improved response to anti-PD-1.

“We studied a small group of patients, but the results were quite suggestive. Our findings need to be confirmed in a prospective study. This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy. Our study will hopefully lead to understanding the biological mechanisms that explain why NRAS mutations predict response,” Dr. Johnson and his associates said.

Patients with advanced melanoma who were treated with immunotherapy responded better if they harbored mutations in the NRAS gene, according to a study published March 3 in Cancer Immunology Research.

Out of 229 cases retrospectively analyzed, 26% had mutations in NRAS^G12/G13/Q61, 23% had BRAF^V600, and 51% were wild type for NRAS and BRAF. Patients received first-line therapy with high-dose IL-2 (25%), ipilimumab (62%), or anti-PD-1/PD-L1 (12%), investigators reported (Cancer Immunol. Res. 2015 March 3).

©benjaminalbiach/ThinkStock

Complete or partial responses were found in 32% of patients with NRAS-mutant melanomas, compared with 20% of those without NRAS mutations (P = .07). Clinical benefit (defined as complete response, partial response, or stable disease for 24 weeks or longer) was observed in 50% of the NRAS mutant group vs. 30% of the non–mutant NRAS group (P < .01), reported Dr. Douglas B. Johnson of Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and associates.

Although the numbers for individual agents were small, the NRAS-mutant benefit was most pronounced for immune checkpoint inhibitors, especially anti-PD-1/PD-L1 therapy, where clinical benefit was observed in 8 of 11 NRAS-mutant patients vs. 13 of 37 patients with wild-type NRAS.

“This finding could have implications for molecular testing and treatment decision making, and it provides early insights into the complex relationship between tumor genetics and the immune response,” Dr. Johnson and associates wrote.

Patients with NRAS-mutant melanoma account for 15%-20% of all melanomas, and the mutation is associated with a poorer prognosis. The authors speculate that elevated PD-1 expression may be a factor in inferior prognosis of NRAS-mutant phenotypes as well as the observed improved response to anti-PD-1.

“We studied a small group of patients, but the results were quite suggestive. Our findings need to be confirmed in a prospective study. This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy. Our study will hopefully lead to understanding the biological mechanisms that explain why NRAS mutations predict response,” Dr. Johnson and his associates said.

Patients with advanced melanoma who were treated with immunotherapy responded better if they harbored mutations in the NRAS gene, according to a study published March 3 in Cancer Immunology Research.

Out of 229 cases retrospectively analyzed, 26% had mutations in NRAS^G12/G13/Q61, 23% had BRAF^V600, and 51% were wild type for NRAS and BRAF. Patients received first-line therapy with high-dose IL-2 (25%), ipilimumab (62%), or anti-PD-1/PD-L1 (12%), investigators reported (Cancer Immunol. Res. 2015 March 3).

©benjaminalbiach/ThinkStock

Complete or partial responses were found in 32% of patients with NRAS-mutant melanomas, compared with 20% of those without NRAS mutations (P = .07). Clinical benefit (defined as complete response, partial response, or stable disease for 24 weeks or longer) was observed in 50% of the NRAS mutant group vs. 30% of the non–mutant NRAS group (P < .01), reported Dr. Douglas B. Johnson of Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tenn., and associates.

Although the numbers for individual agents were small, the NRAS-mutant benefit was most pronounced for immune checkpoint inhibitors, especially anti-PD-1/PD-L1 therapy, where clinical benefit was observed in 8 of 11 NRAS-mutant patients vs. 13 of 37 patients with wild-type NRAS.

“This finding could have implications for molecular testing and treatment decision making, and it provides early insights into the complex relationship between tumor genetics and the immune response,” Dr. Johnson and associates wrote.

Patients with NRAS-mutant melanoma account for 15%-20% of all melanomas, and the mutation is associated with a poorer prognosis. The authors speculate that elevated PD-1 expression may be a factor in inferior prognosis of NRAS-mutant phenotypes as well as the observed improved response to anti-PD-1.

“We studied a small group of patients, but the results were quite suggestive. Our findings need to be confirmed in a prospective study. This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy. Our study will hopefully lead to understanding the biological mechanisms that explain why NRAS mutations predict response,” Dr. Johnson and his associates said.