The depth of mutational agony and the exuberance of tumoral T cell ecstasy predict checkpoint salvation

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Science Immunology  07 Dec 2018:
Vol. 3, Issue 30, eaav9722
DOI: 10.1126/sciimmunol.aav9722


Genomic biomarkers will help to elucidate which cancer patients will benefit from PD-1 blockade immunotherapy.

Given the successes of immune checkpoint blockade in cancer therapy, there has been significant interest in predicting which patients will or will not respond to treatment. Most studies have focused on a singular aspect of the antitumor immune landscape, investigating an individual biomarker on a specific cancer type. Cristescu and associates performed two parallel analyses to better characterize the multifaceted antitumor response prior to immunotherapy. Intratumoral T cell activity and somatic tumor mutation burden were simultaneously investigated in 315 patient samples encompassing 22 different tumor types. This analysis was conducted on specimens from four separate keynote clinical trials of Merck's anti–programmed cell death protein–1 (PD-1) antibody, pembrolizumab.

T cell activity was investigated with targeted gene expression profiling of tumor RNA, and tumor mutation burden was assessed by whole-exome sequencing in pretreatment samples and correlated with response to therapy. Independently, both biomarker signatures predicted response to pembrolizumab across a variety of cancer types, but interestingly there were only modest correlations between the two biomarker signatures. Although pretreatment antitumor T cell activity and increased tumor neoantigenicity have previously been shown to predict response rates to immunotherapy, by performing both analyses simultaneously on a mixed cohort, Cristescu et al. identified four unique patient groups with subtly distinct response rates for each cancer type. The response rate observed was strongest for patients with a high T cell activity signature and high tumor mutation burden, moderate in patients with a single high biomarker score, and reduced when neither biomarker signature was strong.

Although there are significant survival benefits to a number of patients treated with immune checkpoint blockade, there are also substantial financial costs and severe autoimmune side effects. This complex analysis not only contributes to our understanding of predicting response rates to pembrolizumab for patients, but also helps to establish a framework for analyzing biological material from clinical trials of the next generation of immune checkpoint inhibitors.

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