Advertisement

Current Oncology Reports

, 20:8 | Cite as

From a Patient Advocate’s Perspective: Does Cancer Immunotherapy Represent a Paradigm Shift?

  • Debra L. Madden
Palliative Medicine (A Jatoi, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Palliative Medicine

Abstract

Purpose of Review

In 2016, the American Society of Clinical Oncology (ASCO) announced immunotherapy as the year’s top cancer advance in its “Clinical Cancer Advances 2016: ASCO’s Annual Report on Progress Against Cancer.” Further, ASCO again named “Immunotherapy 2.0” as the 2017 advance of the year, emphasizing the recent, rapid pace of research into new agents that harness and enhance the innate abilities of the immune system to recognize and fight cancers—and stressing that such agents have extended the lives of many patients with late-stage cancers for which there have been few treatment options. This article discusses the history of cancer immunotherapy and the recent promising advances, yet also presents a note of caution on limitations of immunotherapies, their potential harms, and the critical need for oncologists to appropriately engage with and educate patients to effectively manage their expectations.

Recent Findings

Learning how to effectively harness the immune system to treat cancer represents an investigative journey of more than 100 years. However, after many failures and disappointments, this decade has seen several important successes. In 2011, the Food and Drug Administration (FDA) approved the first immunotherapy agent known as a “checkpoint inhibitor.” Beginning in 2014, several additional checkpoint blockage drugs have been FDA-approved, and new indications and drug combinations have emerged. Further, on August 30, 2017, the FDA announced its first approval of a new form of immunotherapy known as CAR T cell therapy. Since the 2011 approval of the first checkpoint inhibitor, cancer immunotherapy research among the pharmaceutical industry and research institutions has exploded, with thousands of clinical trials currently taking place. The current “cancer immunotherapy revolution” is in the headlines daily and is also the primary topic of conversation among major cancer research conferences and symposia attendees. However, a once quiet voice has begun to emerge, where an increasing number of scientists, clinicians, and patient advocates are stressing the need for caution concerning the limitations and potential harms associated with cancer immunotherapy.

Summary

Many oncologists, scientists, medical professional associations, and advocates agree that no recent cancer advance has been as successful, transformative, and potentially paradigm-shifting as immunotherapy. With this decade, we have seen the approval of several immunotherapy agents that have successfully treated a percentage of patients with notoriously resistant cancers, an increasing number of combination immunotherapy treatments, and new indications for approved agents. However, patients need to be aware that much of the popular media has breathlessly inflated positive outcomes of cancer immunotherapies, while neglecting to stress that just a small percentage of patients actually benefit from such treatments. Further, they often completely overlook the unique, potentially life-threatening harms that may be associated with these agents and fail to cover negative findings where immunotherapies have appeared to paradoxically accelerate cancer growth. Fortunately, the majority of journal articles presenting trial results and comprehensive review articles appropriately discuss the important limitations associated with immunotherapies, the unique spectrum of adverse effects, and the need for further research to improve our ability to identify those patients who are most likely to benefit from specific agents, sparing other patients from exposure to agents that will not be effective, yet may carry potentially life-threatening toxicities.

Keywords

Clinical oncology Late-stage cancers Refractive cancers Cancer immunotherapy Solid tumors T cells Checkpoint inhibitors PD-1 checkpoint inhibitors CTLA-4 checkpoint inhibitors Adoptive cell transfer (ACT) CAR T cell therapy Monoclonal antibodies Targeted therapies Cancer vaccines Immune-related adverse events (irAEs) “Pseudo-progression” Cytokine release syndrome (CRS) Patient education Cancer research advocacy Immunotherapy in the media Immunotherapy: hope or hype? 

Notes

Compliance with Ethical Standards

Conflict of Interest

Debra L. Madden was a speaker at the American Journal of Managed Care (AJMC)‘s 5th Annual Patient-Centered Oncology Care meeting, where she gave a presentation from the perspective of a cancer research advocate and cancer survivor called “Immunotherapy: The Promise, the Challenge, and the Patient.” The AJMC covered all travel expenses and issued an honorarium as well. She has also served as a contributor to their website and blogged there with the same focus, but has received no compensation for her blog contributions. She also writes her own blog entitled “Musings of a Cancer Research Advocate,” from which she linked to her AJMC contributions, but has received no compensation for writing her blog.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    A brief history of immunotherapy. Targeted oncology. Published online: Aug 21, 2014. http://www.targetedonc.com/publications/special-reports/2014/immunotherapy-issue3/a-brief-history-of-immunotherapy.
  2. 2.
    Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23.  https://doi.org/10.1016/j.cell.2017.01.017.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–9.  https://doi.org/10.1038/nature10673.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180–3.  https://doi.org/10.1016/S0022-5347(17)58737-6.CrossRefPubMedGoogle Scholar
  5. 5.
    Sylvester RJ. Bacillus Calmette-Guerin treatment of non-muscle invasive bladder cancer. Int J Urol. 2011;18(2):113–20.  https://doi.org/10.1111/j.1442-2042.2010.02678.x.CrossRefPubMedGoogle Scholar
  6. 6.
    •• Burnet M. Cancer—a biological approach. Br Med J. 1957;1(5022):779–86. The author, along with the author cited below, was the first to propose the theory of immunosurveillance, suggesting that tumor cell neoantigens could trigger an effective immune response to eliminate a developing cancer.  https://doi.org/10.1136/bmj.1.5022.779.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dunn GP, Old LJ, Schreiber R. The immunobiology of cancer immunosurveillance and immunoediting. CellPress. 2004 Aug;21(2):137–48.Google Scholar
  8. 8.
    •• Thomas L, Lawrence HS, editors. Cellular and humoral aspects of the hypersensitive states. New York: Hoeber-Harper; 1959. p. 529–32. The author originally proposed the role of immunosurveillance as a primary defense against cancer, theorizing that it was evolutionary in nature and that complex organisms must have immune mechanisms to protect the host against cancer similar to those that resulted in organ transplant rejection. Google Scholar
  9. 9.
    •• Thomas L. On immunosurveillance in human cancer. Yale J Biol Med. 1982;55(3–4):329–33. This article further discusses immuno-protective mechanisms against cancer similar to those that brought about homograft rejection and the problems that resulted in fierce debate concerning whether the human’s natural immune defenses could be protective against non-viral cancers. PubMedPubMedCentralGoogle Scholar
  10. 10.
    Old LJ, Boyse EA, Oettgen HF, DeHarven E, Geering G, Williamson B, et al. Precipitating antibody in human serum to an antigen present in cultured Burkitt’s lymphoma cells. Proc Natl Acad Sci U S A. 1966;56(6):1699–704.  https://doi.org/10.1073/pnas.56.6.1699.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    The Big IF in Cancer: will the natural drug interferon fulfill its early promise? TIME. March 31, 1980.Google Scholar
  12. 12.
    Weltman JK. The 1984 Nobel laureates in medicine (immunology): J.F. Kohler, C. Milstein, N.K. Jerne. N Engl Reg Allergy Proc. 1985;6(1):84–5.  https://doi.org/10.2500/108854185779048906.CrossRefPubMedGoogle Scholar
  13. 13.
    •• Milstein C. The hybridoma revolution: an offshoot of basic research. BioEssays. 1999;21(11):966–73. This narrative article describes how his interest in antibody diversity enabled him to develop somatic cell genetic techniques, ultimately leading to the develop of monoclonal antibodies in vitro.  https://doi.org/10.1002/(SICI)1521-1878(199911)21:11<966::AID-BIES9>3.0.CO;2-Z.CrossRefPubMedGoogle Scholar
  14. 14.
    Nissim A, Chernajovsky Y. Historical development of monoclonal antibody therapeutics. Hand Exp Pharmacol. 2008;181:3–18.  https://doi.org/10.1007/978-3-540-73259-4_1.CrossRefGoogle Scholar
  15. 15.
    Iqbal N, Iqbal N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother Res Pract. 2014;2014:357027–9.  https://doi.org/10.1155/2014/357027.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Baker SJ, Reddy EP. Targeted inhibition of kinases in cancer therapy. Mt Sinai J Med. 2010;77(6):573–86.  https://doi.org/10.1002/msj.20220.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Meric-Bernstam F, Mills GB. Overcoming implementation challenges of personalized cancer therapy. Nat Rev Clin Oncol. 2012;9(9):542–8.  https://doi.org/10.1038/nrclinonc.2012.127.CrossRefPubMedGoogle Scholar
  18. 18.
    Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14(1):73.  https://doi.org/10.1186/s12916-016-0623-5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.  https://doi.org/10.1016/j.immuni.2013.07.012.CrossRefPubMedGoogle Scholar
  20. 20.
    Pickett, JM (2012) Provenge researcher threatened for questioning company studies. ExpertBriefings.com. http://www.expertbriefings.com/news/provenge-researcher-threatened-for-questioning-company-studies/.
  21. 21.
    Anassi E, Ndefo UA. Sipuleucel-T (provenge) injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer. PT. 2011;36(4):197–202.Google Scholar
  22. 22.
    Lichtenfeld L (2008) Kidney cancer vaccine: much hype, little hope. Dr. Len’s Blog. http://blogs.cancer.org/drlen/2008/07/03/kidney-cancer-vaccine-much-hype-little-hope/.
  23. 23.
    Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomized phase II trial. Lancet. 2008;372(9633):145–54.  https://doi.org/10.1016/S0140-6736(08)60697-2.CrossRefPubMedGoogle Scholar
  24. 24.
    •• Yang JC. Vitespen: a vaccine for renal cancer? Lancet. 2008;372(9633):92–3.  https://doi.org/10.1016/S0140-6736(08)60698-4. This article is an editorial that accompanied the kidney cancer vaccine study cited directly above. The editorial’s author took issue with the investigators, since although the study results were negative, showing no evidence that the vaccine significantly decreased time to recurrence in patients with renal cell carcinoma, they did an unplanned post-hoc analysis and included those results in their paper, stating that for those patients with “intermediate-risk” renal cell carcinoma, the vaccine decreased recurrence as compared to control patients. The editorial’s author also outlined the study’s technical failings, emphasized that the study results do not support their hypothesis that the vaccine was beneficial for some patients, and criticized the use of unplanned, post-hoc analyses “to salvage underpowered studies or those that fail to reject the null hypothesis.” CrossRefPubMedGoogle Scholar
  25. 25.
    Dearnent A (2016) Don’t let cancer immunotherapy hope give way to hype. Forbes. https://www.forbes.com/sites/mergermarket/2016/05/23/dont-let-cancer-immunotherapy-hope-give-way-to-hype/#5b1d6dc81183.
  26. 26.
    FDA News Release. FDA approval brings first gene therapy to the United States: CAR T-cell therapy approved to treat certain children and young adults with B-cell acute lymphoblastic leukemia. Aug. 30, 2017; .https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm Accessed September 16, 2017.
  27. 27.
    Hagen T (2017) Novartis sets a price of $475,000 for CAR T-cell therapy. OncoLive. http://www.onclive.com/web-exclusives/novartis-sets-a-price-of-475000-for-car-tcell-therapy
  28. 28.
    •• Ma W, Gilligan BM, Yuan J, Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol. 2016;9(1):47. This article summarizes current knowledge concerning immune checkpoint inhibitors with anti-PD-1 and anti-CTLA-4 monoclonal antibodies in the treatment of advanced solid tumors, including efficacy and the remaining unmet need to develop biomarkers and assays to identify those patients most likely to benefit from immunotherapy and to help avoid irAEs.  https://doi.org/10.1186/s13045-016-0277-y.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomized, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375–84.  https://doi.org/10.1016/S1470-2045(15)70076-8.CrossRefPubMedGoogle Scholar
  30. 30.
    •• Bellmunt J, Powled T, Vogelzang NJ. A review of the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 2017;54:58–67.  https://doi.org/10.1016/j.ctrv.2017.01.007. This article reviews the evolution of the treatment of bladder cancer, focusing on the role of immunotherapy, beginning with the bacterial BCG vaccine to modern checkpoint inhibition with CTLA-4 and PD-L1 inhibitors. CrossRefPubMedGoogle Scholar
  31. 31.
    Immunotherapy in patients with active autoimmune disease. ASCO-SITC Clinical-Immuno-oncology Symposium Daily News. 2017. https://immunosym.org/daily-news/immunotherapy-patients-active-autoimmune-disease.
  32. 32.
    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
  33. 33.
    Postow M, Wolchok J (2016) Toxicities associated with checkpoint inhibitor immunotherapy. UpToDate website. http://www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy. Literature review current through. Updated Jan 6, 2016
  34. 34.
    Gay N, Prasad V (2017) Few people actually benefit from “breakthrough” cancer immunotherapy. Stat News. https://www.statnews.com/2017/03/08/immunotherapy-cancer-breakthrough/
  35. 35.
    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. 2016;351(6280):1463–9.  https://doi.org/10.1126/science.aaf1490.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Begley S. The newest cancer therapies don’t work on everyone. Now, doctors have a clue why. Stat News website. https://www.statnews.com/2016/03/03/cancer-immunotherapy-neoantigens/. Published March 3, 3016. Accessed 21 Mar 2016
  37. 37.
    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. http://cancergrace.org/lung/2015/12/15/gcvl_lu_immunotherapy_response_time_pseudoprogression_concept/
  38. 38.
    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
  39. 39.
    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):237–46.  https://doi.org/10.7497/j.issn.2095-3941.2014.04.002.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Pilones KA, Vanpouille-Box C, Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin Radiat Oncol. 2015;25(1):28–33.  https://doi.org/10.1016/j.semradonc.2014.07.004.CrossRefPubMedGoogle Scholar
  41. 41.
    Kato S, Goodman AM, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyper-progressors afterimmunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242–50.  https://doi.org/10.1158/1078-0432.CCR-16-3133.CrossRefPubMedGoogle Scholar
  42. 42.
    Lahmar J, Mezquita L, Koscielny S, Facchinetti F, Bluthgen MV, Gazzah AA, et al. Immune checkpoint inhibitors (IC) induce paradoxical progress in a subset of non-small cell lung cancer (NSCLC). Ann Oncol. 2016;27(supple_6):1222P.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Debra L. Madden
    • 1
  1. 1.NewtownUSA

Personalised recommendations