C-107 How checkpoint blockade alters the repertoire and function of tumor specific T-cells

Abstract

The past 10 years have seen a transformation in cancer treatment, as immunotherapy has come to fruition after many decades of research. Interestingly, this inflexion point has not been based on stimulation of anti-tumor immunity by agents like vaccines or systemically delivered cytokines, but rather by blockade of inhibitory receptors or their ligands—generally referred to as checkpoints. These advances were highlighted in Science's 2013 “Breakthrough of the Year” and by this year's Nobel Prizes. The success of checkpoint-blocking antibodies demonstrates that many, arguably most, cancer patients contain T cells capable of recognizing and killing their cancer. The most significant checkpoint to be blocked is PD-1, whose ligands are PD-L1 and PD-L2. Three anti-PD-1 and 3 anti-PD-1 antibodies have been approved for treatment of 13 different cancer types. The activity of these antibodies depends on activation of T cells. There are 2 FDA approved biomarkers to identify patients more likely to respond to anti-PD-1. One is expression of PD-L1 and the other is mismatch repair deficiency, which is the cause of 4% of cancers. Mismatch repair deficiency (MMRd also called micro-satellite instability-MSI) results from homozygous inactivation of one of 4 mismatch repair genes. These cancers typically have over 1000 non-synonymous mutations/exome. Because a major target of anti-tumor T cells is mutation-associated “neoantigenic” peptides, patients with MMRd cancers have huge numbers of neoantigens that can be recognized but they are not killed because they are restrained by engaging PD-1. Anti-PD-1 antibodies induce major cancer regressions in over 50% of MMRd cancers, regardless of tissue of origin. Three major endeavors are advancing cancer immunotherapy for the 75%–80% or cancer patients NOT benefitted by monotherapy with anti-PD-1/PD-L1 antibodies: (1) Therapeutic combinations with anti-PD-1 or anti-PD-L1 being foundational, (2) Reversal of T cell dysfunction and (3) Refined development of biomarkers to identify patients most likely to respond to various immunotherapies and their combinations. Recent technologies, including TCRseq, single cell analyses and multispectral imaging are accelerating the identification of new drug targets and biomarkers to promote this endeavor.