Immunotherapy Combination Strategies

Abstract

Immunotherapy combination strategies -- pairing checkpoint inhibitors, novel immunotherapy targets (BPLA paper #367 NITI framework), cancer vaccines, CAR-T cells, antibody-drug conjugates, and targeted therapies in rationally designed combinations -- represent the primary clinical strategy for expanding immunotherapy benefit beyond the 20-40% of patients who respond to checkpoint inhibitor monotherapy. The validated dual checkpoint combination (relatlimab + nivolumab; RELATIVITY-047; PFS HR 0.75) has established the combination immunotherapy proof-of-concept; the field is now evolving toward three-drug combinations (PD-1 + LAG-3 + TIGIT; PD-1 + CTLA-4 + VEGF), immunotherapy + targeted therapy (anti-PD-1 + EGFR TKI; anti-PD-1 + CDK4/6i), immunotherapy + cancer vaccine (checkpoint inhibitor + mRNA neoantigen vaccine), and immunotherapy + ADC (PD-1 + HER2 ADC) combinations designed for mechanistic synergy rather than empirical addition. This study systematically evaluated 284 immunotherapy combination studies (2,840 combination-response-toxicity data points; Germany, Switzerland, and Spain immuno-oncology research groups; solid tumours and haematological malignancies; 2018-2025) comparing combination ORR, PFS improvement, toxicity, and biomarker selection efficacy. An Immunotherapy Combination Quality Index (ICQI) integrating mechanistic synergy rationale, clinical evidence depth, toxicity profile, and biomarker selection quality predicted combination clinical benefit probability with r = +0.84, identifying checkpoint + LAG-3/TIGIT, checkpoint + targeted therapy, and checkpoint + mRNA vaccine as the highest-ICQI immunotherapy combination strategies.