In recent years, cancer immunotherapy has emerged as one of the most promising breakthroughs in treating multiple cancer types. The media is filled with reports on blockbuster immunotherapy results, describing it as the most exciting development in cancer therapies in decades—particularly when contrasted with the many agents approved by the FDA based on small effects, increasing survival by weeks or perhaps months when compared with standard treatments for patients with advanced cancers.
Immunotherapy has understandably been a primary focus of discussion among researchers, clinicians, patient advocates, payers, and other stakeholders at major research conferences and meetings during the past few years, including the annual meetings of the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR). Further, there has been a proliferation of immunotherapy-specific conferences, including last year’s coordinated efforts by AACR, the Cancer Research Institute, the Association for Cancer Immunotherapy, and the European Academy of Tumor Immunology to sponsor the first International Cancer Immunotherapy Conference
. The explosion of interest in this new class of therapies has made the research and development of novel immunotherapies an extremely active field, and some patients with advanced, difficult-to-treat cancers, such as malignant melanomas and lung cancers, are finding hope that such agents may successfully treat or make a meaningful difference in the ability to fight their cancers. In fact, ASCO recently designated immunotherapy as the Top Cancer Advance of the Year in its “Clinical Cancer Advances 2016: ASCO’s Annual Report on Progress Against Cancer
noting that “The continued wave of success with immunotherapies, which has extended beyond just a few tumor types, promises to transform cancer care.”
Immunotherapy is considered promising due to multiple factors:
It is systemic therapy.
It enhances the immune system’s innate ability to recognize and fight cancer cells.
It increases specificity in unleashing the immune system’s ability to recognize, target, and selectively kill cancer cells.
It has the ability to “remember” specific cancer antigens, which may lead to durability of response and longer term protection.
It has the potential to treat multiple traditionally difficult-to-treat cancer types.
Much of the excitement has focused on novel agents called checkpoint inhibitors, which unleash an immune attack directed against cancer cells. The immune system has several checkpoint pathways or “negative regulators” that serve to put the brakes on over-activation of the immune system in normal, healthy tissue. The T cells of the immune system are on constant patrol, seeking signs of infection or disease. Upon encountering other cells, they seek to identify the cell by probing specific proteins on its surface. If the proteins suggest that the cell is infected, cancerous, or toxic, the T cells will mount an attack, and the immune system then begins to increase its immune checkpoint molecules to prevent the attack from harming the body’s healthy tissues. Many cancer cells have the ability to exploit these checkpoint pathways (eg, CTLA-4 and PD-1/PD-L1 pathways), up-regulating the inhibitory immune pathways and blocking or deactivating the immune cells, such that the T cells are unable to recognize the cancerous cells as invading threats, enabling them to grow and proliferate out of control.
The checkpoint inhibitors are designed to release these brakes on the immune system by inhibiting the checkpoint, enabling T cells to mount a more effective attack against cancer cells.
To date, 3 checkpoint inhibitors have received accelerated approval by the FDA, including ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) based on durable responses in patients with advanced non-small-cell lung cancer (nivolumab, pembrolizumab), malignant melanoma (nivolumab, pembrolizumab, ipilimumab [with the latter also approved for stage III melanoma]), and metastatic renal cancer (nivolumab) resistant to other available treatments. For drugs that receive accelerated approval from the FDA, sponsors are required to conduct studies to confirm the anticipated clinical benefit—where the drug will be granted traditional approval if the confirmatory trial results show clinical benefit, or the drug (or the specific indication) may be removed from the market if the confirmatory trial does not demonstrate clinical benefit.
Adoptive T-Cell Therapy
Recent headlines also pronounced that dramatic remissions were reported by immunotherapy researcher and Fred Hutchinson Cancer Research Center oncologist, Stanley Riddell, MD, during this year’s annual meeting of the American Association for the Advancement of Science (AAAS), where he announced extraordinary results in early trials using adoptive T-cell therapy, noting that “The early data is unprecedented.” For such personalized therapy, T cells were obtained from cancer patients, genetically modified and tagged with receptor molecules to help them target specific cancer cells, and then administered back to the patients to boost the immune system’s ability to fight the cancerous cells. Riddell reported that in one study with heavily pretreated patients with advanced blood cancers, treatment eliminated symptoms in 94% of patients with acute lymphoblastic leukemia, patients with other blood cancers had response rates greater than 80%, and more than 50% of patients demonstrated complete remission. Yet severe immune responses developed in 7 patients, resulting in 2 deaths. Riddell said, “There are reasons to be optimistic, there are reasons to be pessimistic,” adding that he and his colleagues believe lowering the T-cell dose may help to reduce the risk of adverse effects. Because the research has not yet been published nor peer reviewed, the results are currently difficult to evaluate.2,3
Immunotherapy From a Patient Advocate’s Perspective
As a cancer research advocate, a key part of my role is focusing on the evidence and the implications for patients, ensuring that medical and scientific information is presented clearly and realistically, and stressing the need for caution in raising the hopes of patients when the data is still early. It is imperative that we gather more mature data on a much larger number of patients to accurately assess efficacy, safety, potential harms, durability of response, and impact on disease progression and overall survival. Due to encouraging and widely heralded results for some patients with previously resistant disease and/or cancers for which there are few treatment options, the fact that immunotherapy is an increasingly active area of research, and growing discussion in the popular media concerning immunotherapy’s promise, it is absolutely crucial to educate cancer patients and their families regarding what to expect from immunotherapy.
Clinicians and investigators must ensure that when considering immunotherapy as part of their treatment and/or as part of a clinical trial, patients and their family members are aware of the following:
Immunotherapy is not for every cancer patient. Because immunotherapy agents enhance immune responses, they can also inflame healthy tissues. Therefore, patients with autoimmune disorders—eg, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, lupus, multiple sclerosis, or sarcoidosis—may not be considered appropriate candidates for immunotherapy. Their immune system is already overactive, attacking the body’s own tissues, and treatment for autoimmune conditions generally comprises agents to suppress the immune system’s activity. Receiving immunotherapy could therefore significantly increase the risk of adverse effects and potential mortality in these patients. Patients who have undergone organ transplantation and/or who have a history of liver damage are similarly not appropriate candidates for immunotherapy.4
Immunotherapy is not effective for every cancer patient. As has been widely reported, some patients have had what appear to be remarkably beneficial responses. Unfortunately, what has been less commonly noted is that many cancer patients may not respond to an immunotherapy regimen. Research suggests that tumors with a high number of mutations—eg, lung cancer and malignant melanoma—tend to respond much more effectively, whereas those with fewer genetic mutations may be much more difficult to treat with immunotherapy. In fact, a new study published in Science has found that responders tend to have a large number of mutations producing molecules that move to the tumor cell surface, known as neoantigens. Or, if responders have a low number of neoantigens, they tend to express those throughout the tumor in nearly all tumor cells, rather than in only a limited number of cancerous cells. Since these neoantigens are on the cell surface and are foreign—and because checkpoint inhibitors serve to release the brakes on T-cell activity—the T cells are able to recognize and attack the cancerous cells. The lack of response in the majority of patients is thought to be due to insufficient numbers of neoantigens throughout the tumor to attract T cells.5,6
The time to respond and the nature of such response to immunotherapy is variable. Though response to standard chemotherapy may be seen in weeks, for those receiving immunotherapy who have a clinical response or reduction in tumor burden, response may usually become apparent about 2 months after initiating treatment. In rare cases, for patients with palpable tumors, lesions may reduce in size in days. In addition, time to response may vary between different immunotherapy agents. Importantly, some patients may experience “pseudo-progression,” where if there is a response and immune cells infiltrate the tumor, it may initially appear to grow larger, followed by a subsequent decrease in tumor burden. Further, for some patients, the response may be ambiguous, where multiple cancerous areas have improved on treatment yet a new lesion or lesions developed, or one area has grown whereas the others improved. In such cases, if patients are doing well clinically while on treatment, the medical team may consider keeping them on treatment and continue to monitor response. 4,7,8
Due to different tumor response patterns with immunotherapy agents as contrasted with traditional cytotoxic agents, new evaluation criteria became necessary. The Response Evaluation Criteria in Solid Tumors (RECIST) and the modified World Health Organization (mWHO) criteria are typically used to evaluate solid tumor response. However, due to the recognition that tumor response patterns to immunotherapy agents differ when compared with conventional therapies, new immune-related Response Criteria (irRC) were developed, based on response patterns seen with ipilimumab (anti–CTLA-4 checkpoint inhibitor) treatment and derived from the mWHO criteria. The irRC criteria incorporate measurable total tumor burden (including the sum of the index lesion and new measurable lesions) and compare total tumor burden in consecutive time-point assessments to baseline assessment. The RECIST and mWHO criteria were developed to assess antitumor activity of chemotherapies, where disease progression indicates therapy failure and discontinuation of the drug. With immunotherapies, because response may occur following evidence of progressive disease on imaging (eg, pseudo-progression), disease progression does not always indicate immunotherapy failure. Therefore, by characterizing the full range of potential responses to immunotherapy agents, use of the irRC criteria can help prevent premature cessation of immunotherapy.8
When response does occur, it may tend to be of prolonged duration, though we do not yet know how long. One of the most exciting and promising benefits of immunotherapy is that it can result in sustained responses. Much lengthier follow-up is needed before we can determine just how long such responses are. However, there is a reasonable expectation that for those who previously progressed on standard therapies, the duration of immunotherapy response to checkpoint inhibitors, for example, will exceed that from chemotherapy agents. In addition, data to date suggest that following completion of checkpoint inhibition treatment, the immune system continues to produce an inhibitory effect and that benefit may last for years without the need for continued treatment.
Immunotherapy is an extremely promising addition to cancer therapies, but it does not replace all other treatments. As we learn more and develop new techniques to predict which tumors are most likely to respond to immunotherapy, the greater is its promise for an increasing number of patients. While research efforts are ongoing to discover biomarkers that can identify potential responders, immunotherapy may not be appropriate for every patient, and it is not likely to replace effective traditional chemotherapy regimens and targeted therapies for many cancers.9
In Part II of this article, Ms Madden will discuss the unique spectrum of adverse events that may result from immunotherapy—and why patient education concerning the potential for such effects is crucial.
Optimal benefit will most likely result from combining immunotherapy with other anticancer treatments, including other immunotherapeutics (eg, combined checkpoint inhibition), targeted therapies, or radiotherapy. All therapies have limitations, which in some cases may be overcome via combination strategies. Targeted therapies tend to be associated with high response rates that unfortunately may be short term in some cases, while immune checkpoint inhibitors may have a low, yet sustained, response rate. Combining immunotherapy and targeted therapy could result in a synergistic and improved response. In addition, recent research suggests that radiation therapy promotes the recruitment and enhances function of T cells, complementing checkpoint inhibitor activity. However, additional research on appropriate sequencing, timing, and potential increases in toxicity with combination therapies is vital.10,11
1. Dizon DS, Krilov L, Cohen E, et al. Clinical cancer advances 2016: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol
. 2016;34(9):987-1011. doi:10.1200/JCO.2015.65.8427.
2. Feltman R. Why it’s too early to get excited about this “unprecedented” new cancer treatment. The Washington Post
. Published February 16, 2016. Accessed March 21, 2016.
3. Yuhas A. Cancer researchers claim “extraordinary results” using T-cell therapy. The Guardian
. Published February 15, 2016. Accessed March 21, 2016.
4. Green LM. Immunotherapy in cancer care: educating patients about what to expect. Oncology Nursing News website. http://nursing.onclive.com/publications/oncology-nurse/2015/june-2015/immunotherapy-in-cancer-care-educating-patients-about-what-to-expect#sthash.FeNfHPaO.dpuf
. Published June 30, 2015. Accessed March 21, 2016.
5. McGranahan N, Furness AJS, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockage [published online March 3, 2016]. Science
6. Begley S. The newest cancer therapies don’t work on everyone. Now, doctors have a clue why. StatNews website. https://www.statnews.com/2016/03/03/cancer-immunotherapy-neoantigens/
. Published March 3, 3016. Accessed March 21, 2016.
7. Garron E. Time to response to immunotherapy and the concept of pseudoprogression (video transcript). Global Resource for Advancing Cancer Education website. Published December 15, 2015. Accessed March 22, 2016. http://cancergrace.org/lung/2015/12/15/gcvl_lu_immunotherapy_response_time_pseudoprogression_concept/
8. Assessing immunotherapy response—why irRC matters: clinical optimization. Institute for Clinical Immuno-Oncology website. http://accc-iclio.org/resources/assessing-immunotherapy-response-why-irrc-matters/
. Published June 25, 2015. Accessed March 22, 2016.
9. West H. 5 key points on immune checkpoint inhibitors for lung cancer: game changer or just leveling up? Global Resource for Advancing Cancer Education website. Published January 5, 2014. Accessed March 21, 2016. http://cancergrace.org/lung/2014/01/05/5-key-points-on-immunotherapy-for-lc/
10. Kim T, Amaria RN, Spencer C, Reuben A, Cooper ZA, Wargo JA. Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma. Cancer Biol Med
. 2014;11(4):237-246. doi:10.7497/j.issn.2095-3941.2014.04.002.
11. Pilones KA, Vanpouille-Box C, Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin Radiat Oncol
. 2015;25(1):28-33. doi:10.1016/j.semradonc.2014.07.004.