Antoni Ribas, MD, PhD
Checkpoint blockade immunotherapy has been hailed as a significant advance in anticancer treatment. Yet only a subset of patients experience long-term cancer remission as a result of these therapies, because a significant number of those who initially respond eventually develop resistance.
Why do some patients and not others develop resistance? How can primary and acquired resistance to immunotherapy be overcome? These questions are drawing intense interest from the research community. As investigators seek to unravel the mechanisms of acquired resistance, they also hope to shed light on the components of primary resistance.
The biological and genetic processes that may contribute to relapses were a lively area of inquiry during the 32nd Annual Meeting of the Society for Immunotherapy of Cancer (SITC), held November 8-12 in National Harbor, Maryland. Investigators reported findings about a variety of diagnostic tools to monitor immune responses throughout the treatment cycle in preclinical settings, and about the results of explorations into novel therapies and combinations.
"There’s very little so far that we understand about mechanisms of acquired resistance to immune checkpoint inhibitors,” said Katerina Politi, PhD, an associate professor in Yale University’s Department of Pathology and the Yale Cancer Center, in an interview with OncologyLive®.
Since these therapies are a relatively new modality in clinical practice, the prevalence of acquired resistance among patients treated with these agents is unclear. “I’m not sure we know how many patients are affected by acquired resistance,” Politi said. “It might be different for different cancers.”
Politi, who served as a co-chair of a session on immunotherapy resistance at the SITC conference, has used genetically engineered mouse models to study genetic changes in lung cancer that cause resistance to targeted therapies; now, she is exploring cellular changes that may cause or contribute to resistance to immunotherapy.
Politi’s team is studying tumor specimens before treatment is administered and after resistance develops to determine differences at the DNA or RNA level, and in proteins and immune cells. They are using patient-derived tumor xenografts to understand the impact of the alterations they identify. “We want to be able to validate them functionally,” she said.
Definition and Magnitude of Resistance
Antoni Ribas, MD, PhD, a leading authority on immunotherapy and a Giants of Cancer Care® awardwinner, and colleagues have defined 3 types of resistance to immunotherapy that have been manifested in clinical scenarios: (1) primary resistance, in which the cancer fails to respond to therapy; (2) adaptive immune resistance, in which cancer cells are recognized by the immune system but develop ways to protect themselves from attack (may be primary resistance, mixed response, or acquired resistance); and (3) acquired resistance, in which a cancer responds to immunotherapy but progresses after a period of time.1
The mechanisms that cause these responses are dynamic; they can evolve in response to environmental and genetic factors and to treatment interventions including surgery, chemotherapy, radiation therapy, and immunotherapy. Notably, they may exist prior to the administration of immunotherapy.1
As of November 12, the FDA had approved 6 checkpoint blockade immunotherapy agents: ipilimumab (Yervoy), an anti–CTLA-4 antibody; nivolumab (Opdivo) and pembrolizumab (Keytruda), both anti–PD-1 antibodies; and atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), all anti–PD-L1 antibodies. These agents were approved based on clinical trials that demonstrated overall or objective response rates ranging from approximately 11% to nearly 70%; in many of the studies, the median duration of response was not reached (Table 1).2
Table. Checkpoint Immunotherapy Response Rates and Duration in Pivotal Trials2
Long-term survival rates for patients with melanoma or non–small cell lung cancer (NSCLC) who were treated with anti–PD-1 inhibitors in early clinical trials exceed what would have been expected with standard therapies in these disease settings. Forty percent of patients with advanced melanoma who started taking pembrolizumab during the clinical trial that led to its initial approval were alive after 3 years, researchers reported at the 2016 American Association of Clinical Oncology Annual Meeting.3