T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma

BACKGROUND. Immune checkpoint inhibitors provide significant clinical benefit to a subset of patients, but novel prognostic markers are needed to predict which patients will respond. This study was initiated to determine if features of patient T cell repertoires could provide insights into the mechanisms of immunotherapy, while also predicting outcomes. METHODS. We examined T cell receptor (TCR) repertoires in peripheral blood of 25 metastatic pancreatic cancer patients treated with ipilimumab with or without GVAX (a pancreatic cancer vaccine), as well as peripheral blood and tumor biopsies from 32 patients treated with GVAX and mesothelin-expressing Listeria monocytogenes with or without nivolumab. Statistics from these repertoires were then tested for their association with clinical response and treatment group. RESULTS. We demonstrate that, first, the majority of patients receiving these treatments experience a net diversification of their peripheral TCR repertoires. Second, patients receiving ipilimumab experienced larger changes in their repertoires, especially in combination with GVAX. Finally, both a low baseline clonality and a high number of expanded clones following treatment were associated with significantly longer survival in patients who received ipilimumab but not in patients receiving nivolumab. CONCLUSIONS. We show that these therapies have measurably different effects on the peripheral repertoire, consistent with their mechanisms of action, and demonstrate the potential for TCR repertoire profiling to serve as a biomarker of clinical response in pancreatic cancer patients receiving immunotherapy. In addition, our results suggest testing sequential administration of anti-CTLA-4 and anti-PD-1 antibodies to achieve optimal therapeutic benefit.