Sustained oligoclonal T cell expansion correlates with durable response to anti-PD1 therapy.

Abstract

3061 Background: Immune checkpoint blockers have demonstrated durable response in many tumor types including lung cancer. This clinical benefit is however restricted to a subset of patients in whom longitudinal assessments of their tumor microenvironment have revealed increase CD8+ T cell infiltration. However detailed characterization of this T cell dynamics at clonal levels in a large population of patients is yet to be reported. Such analyses will provide vital insight into the mechanism of tumor eradication in responders. Methods: We performed next-generation sequencing of T cell receptor β chain in longitudinal tumor and peripheral blood samples obtained from lung cancer patients treated with immunotherapies. We first extracted RNA from these samples and synthesized cDNA with 5’RACE adapter using SMART library construction kit (Clontech). We then amplified TCR β gene products to prepare sequence libraries which were analyzed with MiSeq system (Illumina). Results: Here we report on TCR receptor β chain sequencing data for 29 patients in whom we had 3 or more serial samples. Thirteen (45%) of the selected patients in this cohort had durable response and seven (24%) had radiological complete response. We confirmed that there is concordance between the expanded T cell clone at tumor site and the peripheral blood. In one responder, we found expansion of a dominant T cell clone (20%) at a metastatic site where he had pathological complete response on day 17 of treatment and the same clone remained persistent in his peripheral blood (24%) at week 48 of therapy. Similarly in other responders, there were T cell clonal expansions detected as early as week 2 after only one cycle of treatment and such clones remained at high frequencies several months afterwards. Such pattern of early and sustained clonal expansions were absent among non-responders even while they remained on therapy. Conclusions: We found durable response to immune checkpoint blockade to correlate with early and sustained expansion of one to two dominant T cell clones in this selected patient cohort.