P3.02c-058 In-Depth Molecular Characterization of T Cell Clonal Expansion Induced by Anti-PD1 Therapy in NSCLC: Topic: IT Biomarkers

Abstract

Inhibitors of PD1/PD-L1 checkpoint have been shown to be active among a broad range of cancers including NSCLC. They induce proliferation of T cells within the tumor microenvironment (as revealed by IHC) leading to tumor eradication. There is however lack of detailed molecular characterization of these proliferating T cells including the dynamics of their clonalilty during treatment and its correlation with response, their antigen specificity and the molecular changes induced in the expanded clones at single cell level. Such understanding will serve as a biomarker to detect early response after one dose of therapy, ascertain efficacy (especially when radiological assessments are equivocal) and guide determination of optimal duration of therapy. Furthermore, insight into molecular changes in the proliferating T cell clones induced by these agents at single-cell level will identify the baseline unique characteristics of T cells clones that undergo rapid expansion upon exposure to anti-PD1 therapy, define the molecular mediators of tumor eradication in responders and serve as a foundation for the development of novel treatment strategies for non-responders. We performed next-generation T cell receptor alpha/beta chain sequencing on serially obtained tumor and PBMC samples from 54 NSCLC patients undergoing anti-PD1 therapy. We compared the dynamics of the T cell repertoire in responders versus non-responders within unsorted PBMC and in CD8 positive/negative T cells. We also assessed the expression of key mediators of cytotoxicity and T cell activation/dysfunction in these expanded CD8 T cell clones at single cell level among responders and non-responders. We identified concordant early clonal T cell expansion after 1-4 doses of anti-PD1 therapy within the tumor and PBMC of responders. We confirmed these expanded T cell clones to be CD8 positive subgroup of CD3+ T cells in responders and CD8 negative subgroup of CD3+ T cells in non-responders. Furthermore, among responders we found that persistence of the expanded T cell clones for several months while on treatment is associated with durable response. Additional results on antigen specificity and gene expression of the expanded T cell clones in responders versus non-responders will be presented. Our results showed that early concordant clonal expansion of a defined population of CD8+ T cells detected both within the tumor and PBMC correlate with response to therapy. We also confirmed that the persistence of these unique T cell clones several months after their initial expansion correlates with durable response.