CD4+ T cells and neoantigens in melanoma immunotherapy.

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PROJECT ABSTRACT Recent clinical trials, using checkpoint blockade, antigen-specific T cell receptor (TCR) or CD19-chimeric antigen receptor (CAR), have shown promising clinical results for patients with metastatic cancer. However, despite the impressive and durable clinical response in cancer patients treated with anti-PD-1 antibody, more than 50% of cancer patients fail to respond to this checkpoint blockade treatment. Immunotherapy based on vaccines and TCR in many solid tumors is still lacking due to lack of tumor-specific targets. Therefore, new targets and strategies are urgently needed for the development of immunotherapeutic approaches for solid tumors including melanoma. Whole exome sequencing approach in combination with computer-assisted prediction algorithms has provided an exceptional opportunity to identify new patient-specific antigen targets for cancer immunotherapy. By taking advantage of next-generation sequencing and tumor-reactive T cells, we recently identified many neoantigens recognized by tumor-reactive CD4+ T cells as well as CD8+ T cells. Importantly, we found that some of CD4+ T clones with a single TCR could recognize multiple neoantigens, but not the corresponding wild-type antigens. Recent clinical studies show that mutation-specific CD4+ T cells can mediate tumor growth inhibition in melanoma and epithelial cancers, suggesting that CD4+ T cells play a critical role in inhibiting tumor growth and orchestrating overall antitumor immunity. However, clinical responses of cancer patients are correlated with the trafficking, persistence and cytotoxic ability of T cells. We show that CD4+ T cells can be reprogrammed to increase their cytotoxicity activity against cancer cells. Based on these premises, we hypothesize that neoantigen-specific T cells, in particular CD4+ T cells, play an important role in recognizing neoantigens that drive tumor-specific antitumor immunity, leading to tumor regression. These neoantigens can be identified from melanoma and exploited as therapeutic targets for immunotherapy. We further hypothesize that neoantigen-specific CD4+ T cells can be engineered for improving their T cell persistence and cytolytic activity in combination with anti-PD-1 blockade. Based on these premises, we propose to identify novel neoantigens with emphasis on MHC class II neoantigens using genome-wide sequencing analysis and a genetic targeting expression system (Aim 1). We further plan to investigate whether potent therapeutic antitumor immunity can be generated by immunodominant neoantigen and a novel SAPNANO vaccine technology (Aim 2). Finally, we pursue our studies to determine whether SAPNANO vaccine-induced or T cell transfer immunity can be further enhanced by immune checkpoint blockade or reprogramming T cells to improve their cytotoxicity, (Aim 3). In all, the successful completion of our proposed studies will potentially shift the paradigm by the development of novel immunotherapies for many types of cancer including melanoma.