Editorial


A new hope


R. Wong, BSc MD*


doi: http://dx.doi.org/10.3747/co.27.6035

Immuno-oncology uses the body’s inherent immune system to combat malignancy. It is one of the most promising new avenues of treatment for the millions of people worldwide who are experiencing cancer. For many years, the immune system has been known to play an important role in the regulation of cancer. Patients who are immunosuppressed experience a higher incidence of malignancy, and the incidence of spontaneous remission in a variety of cancers is approximately 1 in every 60,000 to 100,000 cases1,2. Possibly the earliest example of immunotherapy is noted in the Ebers Papyrus (ca. 1550 bce), attributed to the legendary Egyptian physician Imhotep (ca. 2600 bce). In it, the recommended treatment for swellings (tumours) is the application of a poultice, followed by an incision. Such a treatment would lead to an infection at the site of the tumour and regression3.

In 1891, an American surgeon, William B. Coley, first attempted to harness the immune system for treating cancer4,5. After noting responses in cancer patients who developed erysipelas, Coley injected heat-inactivated bacteria (“Coley toxins”) directly into tumours and achieved a significant number of regressions and durable complete responses in his patients6. However, because of a number of factors, including failure to follow appropriate scientific protocols, inconsistent results, severe side effects, and the development of radiation therapy and chemotherapy, Coley’s techniques gradually disappeared from clinical practice. However, in 1976, his strategy resurfaced when bacillus Calmette–Guérin was found to be effective in the treatment of superficial bladder cancer7.

In the decades that followed, progress in immunotherapy remained quite slow, with only the approvals for two nonspecific immunostimulatory cytokines: interleukin 2 and interferon. Both were associated with limited efficacy and significant toxicity. However, long-term remissions or cures were noted in melanoma and renal cancer. Interferon alfa was approved in 1986 for hairy cell leukemia, chronic myelogenous leukemia, follicular non-Hodgkin lymphoma, melanoma, and aids-related Kaposi sarcoma. Interleukin 2 was approved for the treatment of renal cancer in 1991 and for melanoma in 1998. Immunotherapy began to change with the description of PD-18,9 and the isolation of ctla-4 and determination of its function10,11—two watershed events that allowed for the development of checkpoint inhibitors. However, it would be 14 years before the first phase iii clinical trials definitively showed the benefits of those agents, allowing for their approval by regulatory bodies12.

At approximately the same time, Carl June and colleagues used a chimeric antigen receptor T cell strategy to produce a complete and durable remission in a pediatric patient with treatment-refractory chronic lymphocytic leukemia after adoptive transfer of construct-transduced autologous T cells13. Immuno-oncology had entered the 21st century.

In 2013, Science declared cancer immunotherapy to be the “Breakthrough of the Year”14. Since that time, the field of immuno-oncology has grown rapidly, now being used in the treatment of a wide range of malignancies. Its impact is being felt by all specialists involved in the management of patients with cancer, and the benefits to those patients have been nothing short of extraordinary.

The introduction of immunotherapy into Canada has not been without its challenges: Patients with hitherto untreatable and incurable cancers are now routinely being offered treatment, straining already-limited resources and treatment beds. For example, before 2010, almost all patients with stage iv melanoma were not offered systemic therapy. Now almost all are receiving some form of treatment, which, in some cases, is bringing their disease under control for a long period of time. The impact is even greater in the more common tumours such as lung cancers. With those successes in the metastatic setting, immunotherapy has now moved into the adjuvant setting, putting additional strain on resources1518.

From my personal perspective as a melanoma specialist, the combinations of new metastatic and adjuvant therapies have roughly quadrupled my workload since about 2010. The side effect profile of some of the immunotherapy therapies are quite favourable19. As a result, patients who would never have been considered for systemic therapy now have that option. In cancer clinics, a number of otherwise healthy patients in their late 80s and early 90s are receiving immunotherapy and achieving control of their disease. The cost of the new treatments has also placed a strain on Canada’s ability to fund them. A disconnect is evident between immunotherapies approved by Health Canada and those that are funded by health payers. With some therapies priced in the hundreds of thousands of dollars, difficult decisions will have to be made with respect to the groups of patients that will receive treatment.

In this Clinical Oncology supplement dedicated to immuno-oncology, we have gathered some of the leading experts in Canada to discuss the many issues that physicians face daily in this new therapeutic field. The supplement presents an overview of the mechanism of action of this new class of drugs; the impact these agents are having in a variety of cancers, including melanoma, lung cancer, genitourinary tumours, and hematologic malignancies; management of the novel side effects attending the use of immunotherapy; promising new treatments, including chimeric antigen receptor T cells; and future directions in the field. I hope that the supplement will provide an excellent overview of the current state of the art in this exciting new area of cancer therapy.

CONFLICT OF INTEREST DISCLOSURES

I have read and understood Current Oncology’s policy on disclosing conflicts of interest, and I declare the following interests: I have received fees as an advisory board member for Bristol–Myers Squibb, Novartis, and Sanofi Genzyme.

AUTHOR AFFILIATIONS

*St. Boniface General Hospital, Winnipeg, MB.

REFERENCES

1 Zafar SY, Howell DN, Gockerman JP. Malignancy after solid organ transplantation: an overview. Oncologist 2008;13:769–78.
cross-ref  pubmed  

2 Salman T. Spontaneous tumour regression. J Oncol Sci 2016;2:1–4.

3 Jessy T. Immunity over inability: the spontaneous regression of cancer. J Nat Sci Biol Med 2011;2:43–9.
cross-ref  pubmed  pmc  

4 Wiemann B, Starnes CO. Coley’s toxins, tumor necrosis factor and cancer research: a historical perspective. Pharmacol Ther 1994;64:529–64.
cross-ref  

5 Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci 1893;105:487–511.
cross-ref  

6 Coley WB. The treatment of sarcoma with the mixed toxins of erysipelas and Bacillus prodigiousus. Boston Med Surg J 1908;158:175–82.
cross-ref  

7 Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette–Guerin in the treatment of superficial bladder tumors. J Urol 1976;116:180–3.
cross-ref  pubmed  

8 Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11:3887–95.
cross-ref  pubmed  pmc  

9 Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996;8:765–72.
cross-ref  pubmed  

10 Krummel MF, Allison JP. CD28 and ctla-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995;182:459–65.
cross-ref  pubmed  pmc  

11 Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by ctla-4 blockade. Science 1996;271:1734–6.
cross-ref  pubmed  

12 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–23.
cross-ref  pubmed  pmc  

13 Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N Engl J Med 2011;365:725–33.
cross-ref  pubmed  pmc  

14 Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013;342:1432–3.
cross-ref  pubmed  

15 Reck M, Rodríguez-Abreu D, Robinson AG, et al. on behalf of the keynote-024 investigators. Pembrolizumab versus chemotherapy for PD-L1–positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–33.
cross-ref  pubmed  

16 Antonia SJ, Villegas A, Daniel D, et al. on behalf of the pacific investigators. Durvalumab after chemoradiotherapy in stage iii non-small-cell lung cancer. N Engl J Med 2017;377 1919–29.
cross-ref  pubmed  

17 Weber J, Mandala M, Del Vecchio M, et al. on behalf of the CheckMate 238 collaborators. Adjuvant nivolumab versus ipilimumab in resected stage iii or iv melanoma. N Engl J Med 2017; 377:1824–35.
cross-ref  pubmed  

18 Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage iii melanoma. N Engl J Med 2018;378:1789–1801.
cross-ref  pubmed  

19 Wang Y, Zhou S, Yang F, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol 2019;5:1008–19.
cross-ref  pubmed  pmc  


Correspondence to: Ralph Wong, Oncology Administration, 409 Taché Avenue, Winnipeg, Manitoba R2H 2A6. E-mail: rwong2@cancercare.mb.ca

(Return to Top)



Current Oncology, VOLUME 27, Supp. 2, April 2020