High peripheral T cell diversity is associated with lower risk of toxicity and superior response to dual immune checkpoint inhibitor therapy in patients with metastatic NSCLC

Introduction Despite significant successes, immune checkpoint blockade fails to achieve clinical responses in a significant proportion of patients, predictive markers for responses are imperfect and immune-related adverse events (irAEs) are unpredictable. We used T-cell receptor (TCR) sequencing to systematically analyze prospectively collected patient blood samples from a randomized clinical trial of dual immune checkpoint inhibitor therapy to evaluate changes in the T-cell repertoire and their association with response and irAEs. Methods Patients with immunotherapy-naïve metastatic non-small cell lung cancer (NSCLC) were treated with ipilimumab and nivolumab according to trial protocol (LONESTAR, NCT03391869). Blood samples were systematically obtained at baseline (n=107), after 12 weeks of ipilimumab and nivolumab (n=91), and at the time of grade ≥2 irAEs (n=77). For analysis of T-cell repertoire, we performed immunoSEQ to assess the complementary determining region 3β region of the TCR involved in antigen binding. Results A total of 250 samples from 119 patients were analyzed. Patients who had a response to therapy exhibited greater T-cell diversity at baseline. Interestingly, patients with irAEs demonstrated lower T-cell richness at the time of toxicity compared with those without irAEs. Conclusion Our study highlights the potential impact of peripheral blood T-cell repertoire on clinical response and toxicities from the combination of ipilimumab and nivolumab in patients with metastatic NSCLC. These findings suggest that analysis of peripheral blood T-cell repertoire may help to guide patient selection for treatment with ipilimumab and nivolumab.