Ratio of Certain Immune Cells in the Blood to Tumor Burden Correlated With Outcome for Melanoma Patients Treated With Pembrolizumab
Although some patients with melanoma experience durable responses to treatment with the anti–PD-1 (programmed cell death protein 1) therapy pembrolizumab (Keytruda), the majority of patients do not experience a durable clinical benefit from anti–PD-1 monotherapy, according to a study by Huang et al. To determine the underlying reasons for the successful response vs treatment failure of anti–PD-1 therapy in patients with advanced melanoma, they investigated whether it was possible to predict a patient’s response to pembrolizumab by tracking the effect of the drug on immune cells in blood samples taken from patients. They found that the ratio of a subset of immune cells in the blood to tumor burden correlated with clinical response.
The findings provide a framework for analyzing distinct types of treatment failures in melanoma and have implications for stratifying patients into additional immunotherapeutic approaches. The study (abstract 16-A-132-IMM) was presented at the International Cancer Immunotherapy Conference: Translating Science Into Survival on September 25–28, 2016, in New York City. The conference was cosponsored by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research.
Study Methodology
The researchers used detailed immune profiling of peripheral blood samples from 29 patients with stage IV melanoma taken before and at 3, 6, 9, and 12 weeks after starting treatment with pembrolizumab. They then measured levels of the proliferation marker Ki67 in immune cells called exhausted-phenotype CD8-positive T cells (TEX).
Study Findings
The researchers found that robust induction of Ki67 in this subset of circulating CD8 T cells posttherapy (reinvigoration) occurred in 78% of patients, indicating strong, on-target immunologic effects of PD-1 blockade in most patients. Despite this high immunologic response rate, the objective clinical response rate in this cohort was less than 40%.
Ki67 in CD8 T cells alone did not predict clinical outcomes, and, in fact, higher systemic immune activation at baseline was associated with lower overall survival. Rather, the magnitude of reinvigoration of circulating TEX in relation to the pretreatment tumor burden correlated with clinical response. The researchers identified a TEX reinvigoration to tumor burden ratio, which could be used to predict clinical response and overall survival as early as 6 weeks posttherapy.
Consistent observations were found in a second independent cohort and suggest that clinical failure of PD-1 blockade in many patients may not solely be due to an inability to induce immune reinvigoration, but rather an imbalance between T-cell reinvigoration and tumor burden. As a result, by focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, the researchers identified a clinically accessible predictor of response to PD-1 blockade.
“The findings also provide a framework for dissecting distinct types of treatment failures in melanoma and have implications for stratifying patients into additional immunotherapeutic treatment approaches,” concluded the study authors.
“We set out to investigate whether we could monitor and predict a patient’s response to pembrolizumab by tracking the effect of pembrolizumab on immune cells in blood samples from the patients,” said Alexander Huang, MD, a Clinical Fellow in the Division of Hematology/Oncology and Institute for Immunology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and lead author of the study, in a statement. “We found that we could, which is important because it opens up the possibility that we might one day be able to use blood-based assays to inform clinical care. However, we need to validate our findings in a larger group of patients before this can become a reality.”
This study was funded by the National Institutes of Health, the Penn/Wistar SPORE in Skin Cancer, the Tara Miller Foundation, the Peggy Spiegler Melanoma Research Foundation, the David and Hallee Adelman Immunotherapy Research Fund, the Robertson Foundation/Cancer Research Institute Irvington Fellowship, and the Parker Institute for Cancer Immunotherapy.
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