The Promise of Cancer Immunotherapy: Why Patient Education Is Critical, Part I


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,”1 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: Checkpoint Inhibitors

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:
 
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. 

References

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 website. https://www.washingtonpost.com/news/speaking-of-science/wp/2016/02/16/why-its-too-early-to-get-excited-about-this-unprecedented-new-cancer-treatment/. Published February 16, 2016. Accessed March 21, 2016.
3.      Yuhas A. Cancer researchers claim “extraordinary results” using T-cell therapy. The Guardian website. https://www.theguardian.com/science/2016/feb/15/cancer-extraordinary-results-t-cell-therapy-research-clinical-trials. 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. doi:10.1126/science.aaf1490. 
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.
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