Reinvigoration of Progenitor-Exhausted CD8 T Cells by anti-CTLA-4 Contributes to the Sustained Activity of Combination Checkpoint Blockade

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. We performed multimodal analysis across time in 32 stage IV melanoma patients treated with anti-PD-1, anti-CTLA-4, or anti-PD-1 + anti-CTLA-4 (combination) therapy. Anti-CTLA-4 induced more durable immune responses than anti-PD-1, whereas combination therapy mobilized greater and more sustained immune responses. We developed the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Combination therapy generated clonal effector and exhausted CD8 T cells (T_EX) responses that peaked at 6-9 weeks after treatment. Focused analyses of T_EX in additional cohorts identified that anti-CTLA-4 induced robust expansion and proliferation of progenitor T_EX, which synergized with anti-PD-1 to generate a large and durable reinvigoration of T_EX. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.