Immunotherapy Combination Approaches

At the 1-day Cancer Immunotherapy: A Long Awaited Reality Conference, held at the New York Academy of Medicine on March 27, representatives from biotechnology companies and research clinicians working on immunotherapies discussed the promise of combination immunotherapies in cancer.

Ipilimumab, the anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint antibody, is among the first immunotherapy agents to show improved overall survival in advanced cancer patients. The antibody was approved in 2011 by the US Food and Drug Administration (FDA) for treatment of metastatic melanoma based on a large phase III clinical trial that demonstrated a 4-month increase in median overall survival (6 months in the control arm, 10 months in the ipilimumab treatment arm). At 2 years, 24% of patients were still alive and some were alive as long as 4.5 years.

The next generation of immune checkpoint modulators are currently in late-stage clinical trials. These antibodies target a receptor distinct from CTLA-4, called the programmed death receptor-1 (PD-1) or its ligand, PD-L1. Phase III trials with PD-1 and PD-L1 antibodies are currently ongoing in advanced cancers-melanoma, non–small-cell and small-cell lung cancer, and renal cell cancer. So-called third-generation antibodies, both those that target immune inhibitory pathways such as LAG-3 and TIM-3, as well as agonist antibodies that target co-stimulatory receptors for T-cell activation such as OX40 and 4-1BB, are now beginning to enter the clinic in phase I safety trials.

With a spectrum of these immune checkpoint modulators and other therapies-adaptive T-cell, therapeutic vaccines, and cytokines-and a better understanding of the cross talk between tumors and the immune system, researchers are beginning to explore immunotherapy combinations. The first immune checkpoint combination trial, combining the FDA-approved ipilimumab plus the investigational nivolumab resulted in a higher response rate than either antibody alone in patients with metastatic melanoma. Among the 52 patients who received both therapies concurrently, 40% had an objective response. A prior phase I trial of nivolumab in metastatic melanoma resulted in a 28% response rate. Although response rates cannot be directly compared between trials, the authors suggest that both the more rapid kinetics of response and relatively high frequency of response provide promise for better efficacy of this combination. A phase III clinical trial in advanced melanoma is currently ongoing.

Panel members from PDS Biotechnology, Agenus, and Heat Biologics, as well as Holbrook Kohrt, MD, PhD, assistant professor in the division of oncology and immunologist at Stanford University School of Medicine, discussed combination strategies and their rationale. The panelists agreed that combinations of cancer immunotherapies could provide incremental or synergistic survival benefit for patients.

Preclinical models are showing the potential for better efficacy when combining immunotherapies with different mechanisms of action. Adjuvants and vaccines alone have so far not resulted in efficacy in advanced tumors, but the stimulation of the immune system by these agents may be blocked by downstream inhibitory signals, which may need to be themselves inhibited as part of combination therapies. With the large number of immunotherapies in development, researchers and companies that are developing these agents will need to devise smart screening strategies to identify efficacious therapies before embarking on costly clinical trials. Tumor types, such as melanoma and renal cell cancer, which have relatively high levels of tumor infiltrating lymphocytes (TILs) that work within the tumor microenvironment against the tumor, are more likely to respond to immune checkpoint antibodies. One emerging hypothesis is that other tumor types with lower TIL levels may require an additional immunotherapy on top of a CTLA-4, PD-1, or PD-L1 antibody for response.

“I think for the first time we really need to define our patient populations not by the tumor type but how immune-competent the patients are,” said Kohrt. “If a patient has a non-immunocompetent tumor, then we need to figure out how to use therapies to make the switch to make the patient immunocompetent by modifying the checkpoints that are being modulated by the tumors.”

Safety is an important issue when it comes to combination immunotherapies. Although the ipilimumab plus nivolumab clinical trial resulted in robust responses, 93% of these patients had a treatment-related adverse event-72% of these were serious grade 3/4 events. However, the mouse model of this combination did not predict the high level of adverse events seen in patients. “One of the limitations of preclinical models is that they do not recapitulate the toxicities we see in the clinic with combination therapies,” said Kohrt. Kohrt called on the community to provide new strategies for how to design better models that could provide data on the human safety profile potentials of immunotherapies. “We need to learn more about the toxicity patterns of these agents.”

The 4th Annual Cancer Immunotherapy: A Long Awaited Reality Conference at the New York Academy of Medicine in New York City was sponsored by MaidStone Life Sciences LLC.