Keeping Pace With the Immunotherapy Revolution

IN THE LATE 1970s

, a member of my family underwent treatment for breast cancer. As she navigated the rigors of her treatment with a modified radical mastectomy and adjuvant chemotherapy (administered then without the effective antiemetic regimens of today), I recall the toll exacted upon her. Two decades later, as a fellow in bone marrow/hematopoietic cell transplantation, I recalled her experience as we attempted to push the boundaries of dose intensity in an attempt to more effectively care for patients with advanced, relapsed, and persisting malignancies. The side effects of these ever more intensive regimens proved challenging to many patients, and the experience showed us that increasing therapeutic intensity was ultimately limited in its potential effectiveness and applicability.

The quest for more effective cancer treatments has inspired generations of basic science researchers, medical oncologists, surgeons, and radiation oncologists to seek more effective and less morbid ways of treating patients. The extraordinary iterative efforts of basic scientists, physician investigators, and the pharmaceutical industry have led us to identify novel approaches outside the traditional triad of surgery/chemotherapy/radiation therapy for more effective treatment of patients with cancer. It is in this spirit of discovery and innovation that immuno-oncology has arisen as an essential avenue toward the more effective treatment of patients affected by a broad array of cancers.

Investigators, in the early 1970s, had identified immune mediators as a potentially important set of tools for treating patients with cancers. During this period, Time magazine heralded the availability of these “magic bullets” as potential game-changing medications for patients affected by chemotherapy-refractory tumors, such as melanoma and renal cell cancer. The actual effectiveness of interleukin-2 and lymphokine-activated killer cells never quite fulfilled the promise of the Time cover story, but they did showcase the potential importance of the immune system in cancer treatment.^1,2

Flash forward 40 years, and a Google search of the term “immuno-oncology” yields more than 531,000 hits. The glimmer of promise demonstrated by early trials of immunomodulating drugs in the 1970s presaged the current era in which immuno-oncologic agents have been licensed by the FDA at an astonishing rate. The pace of innovation and the increasing breadth of immuno-therapeutic agents over the past 3 decades has accelerated beyond what any of us thought might be possible—the armamentarium has grown to include agents from an astonishingly wide variety of drug classes. These “magic bullets” now include the original set of therapeutic monoclonal antibodies, monoclonal antibody/drug conjugates, bispecific molecules, oncolytic viruses, cancer vaccines, chimeric antigen-receptor (CAR) T-cells, and the growing numbers of checkpoint inhibitors.

It would be difficult to overstate the impact of these new agents in the treatment of a wide variety of cancers. Therapeutic monoclonal antibodies like rituximab and trastuzumab play an indispensable role in the initial treatment of patients with CD20—expressing non-Hodgkin lymphomas and her-2-neu–expressing breast cancers, respectively, resulting in significant improvements in overall survival (OS).^3,4 Monoclonal antibody/drug conjugates, such as brentuximab, have demonstrated the ability to produce remissionsin previously refractory patients with Hodgkin lymphoma and improve OS for high-risk patients following transplantation. Emerging agents in this drug class have demonstrated significant promise in the treatment of patients with relapsed acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia.⁵ The bispecific molecule blinatumomab has been approved for the treatment of patients with refractory and persistent ALL and can serve as an effective “bridge to transplant” for previously untreatable patients.⁶

Beyond the emerging wealth of antibody-based therapeutics, immuno-oncologic innovation now includes treatments based upon the use of oncolytic viruses (T VEC hsv-1 for treatment of melanoma),⁷ cancer vaccines (Sipuleucel-T for treatment of prostate cancer),⁸ and CAR T cell- based therapeutics.⁹ The increasing promise of these agents for treating patients with diagnoses that are typically refractory to standard chemotherapeutic approaches demonstrates the extraordinary promise of these novel therapeutics.

A recent case report in the New England Journal of Medicine published by a research group at the City of Hope, in Duarte, California, demonstrates the potential role for innovative immuno-oncological agents in the treatment of patients for whom therapeutic choices remain limited and largely unsatisfactory.10 In this case report, a patient with recurrent multifocal glioblastoma received intraventricular and tumor cavity—directed injections of CAR T-cells targeted at the interleukin-13 receptor alpha 2—more commonly known as IL13Rα2—as a tumor-associated antigen. The patient achieved a complete response and the response has persisted through the time of publication of the report, 7.5 months after the initiation of CAR T-cell therapy.

These agents are merely the beginning of an immuno-oncological revolution. The emergence of the checkpoint inhibitor class of agents with activity directed at programmed death-1 and programmed death-ligand 1, promise an even more robust armamentarium of immuno-oncological agents in the near term.

It is in this context that we are pleased to bring you this issue of Evidence-Based Oncology™ in which the authors address many important aspects of this brave new field. Experts from the Cardinal Health Specialty Care Solutions provide an overview of CAR T-cell technologies and review how these therapeutics can be successfully integrated into patient care. Jae Park, MD, a CAR T-cell researcher and innovator from Memorial Sloan Kettering Cancer Center, provides his perspective on the value of these therapeutics in answering unmet patient needs. Shawn M. Regis, PhD, a patient navigator with the Lung Cancer Screening Program at Lahey Hospital & Medical Center, describes the various options offered by the hospital via its navigation program and addresses some unique aspects of navigation as it pertains to immuno-oncology. An article from authors at McKesson Specialty Solutions provides insight on how alternative payment models can absorb the impact of innovation in oncology care.

Over the past decade we have seen extraordinary advances in cancer therapeutics that have moved us far beyond what was imaginable early in my career. The idea of harnessing the power of the immune system as a means of bringing more effective, better tolerated treatment solutions to patients in need is deeply inspiring. As we have heard the heightened rhetoric associated with the Cancer Moonshot initiative, the increasing availability of immuno-oncological agents provides concrete evidence that understanding and conquering cancer is achievable. The more prosaic challenge is that of ensuring that as the wealth of new immuno-oncological agents come to market, they are used in an economically sustainable, effective, and patient-centered way.Joseph Alvarnas, MD, is director, medical Quality and Quality, Risk and Regulatory Management, City of Hope. He is also the editor-in-chief of Evidence-Based Oncology™.REFERENCES

1. Lotze MT, Matory YL, Rayner AA, et al. Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer. 1986;58(12):2764-2772.
2. Topalian SL, Rosenberg SA. Therapy of cancer using the adoptive transfer of activated killer cells and interleukin-2. Acta Haematol. 1987;78 (Suppl 1):75-76.
3. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med. 2002;346(4):235-242. doi: 10.1056/NEJMoa011795.
4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. doi: 10.1056/NEJM200103153441101.
5. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753. doi: 10.1056/NEJMoa1509277.
6. Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29(18):2493-2498. doi: 10.1200/JCO.2010.32.7270.
7. Grigg C, Blake Z, Gartrell R, Sacher A, Taback B, Saenger Y. Talimogene laherparepvec (T-Vec) for the treatment of melanoma and other cancers. Semin Oncol. 2016;43(6):638-646. doi: 10.1053/j. seminoncol.2016.10.005.
8. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24(19):3089-3094. doi: 10.1200/JCO.2005.04.5252.
9. Hay KA, Turtle CJ. Chimeric antigen receptor (CAR) T cells: lessons learned from targeting of CD19 in B-cell malignancies [published online January 21, 2017]. Drugs. 2017. doi: 10.1007/s40265017-0690-8.
10. Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561-2569. doi: 10.1056/NEJMoa1610497.

Download PDF: Keeping Pace With the Immunotherapy Revolution