Melanoma is the most aggressive skin cancer and causes over 10,000 deaths per year in the US. While great strides have been made in the treatment of melanoma, many patients are still non-responsive to immunotherapy. Understanding the function of PD1 and LAG3 on the immune response in both the tumor and periphery of patients is critical to the progress of immunotherapy in melanoma. Although LAG3 is the third ‘checkpoint’ to be targeted with >10 agents in clinical trials, we still know very little about how LAG3 blockade, alone or with anti-PD1, impacts the immune response to melanoma. We have demonstrated synergistic PD1/LAG3 combinatorial immunotherapy in mouse models of cancer and clear evidence of clinical benefit from dual inhibitory receptor (IR) blockade has stimulated anti-PD1 and anti-LAG3 trials in cancer patients failing previous immunotherapies. Project 1 includes a novel biomarker-focused phase II randomized clinical trial to evaluate the combination of anti-PD1 (Nivolumab) and/or anti-LAG3 Relatlimab) therapy in treatment naïve melanoma patients. We hypothesize that different transcriptional and functional pathways are regulated by anti-PD1 and anti-LAG3 in CD8+ T cells, and that unique synergistic molecular programs will be revealed by this immunotherapeutic combination. We will assess the mechanistic impact of anti-PD1 and/or LAG3 immunotherapy in peripheral and tumor CD8+ T cells. Based on novel findings, we also hypothesize that cytokine-driven systemic immune dysfunction and subsequent resistance to anti-PD1 therapy is driven by a LAG3-led inhibitory receptor module, and that this dysfunction can be ameliorated by anti-LAG3 blockade.
Collectively, the findings in this application will define new biomarkers of response and resistance to Nivolimab, Relatlimab, and the combination. They will identify a patient population that will optimally benefit from LAG3-based therapies, and support novel combinatorial immunotherapies of increased efficacy in melanoma.