Adoptive cellular therapy and therapeutic cancer vaccines have shown promise in solid tumor malignancies but responses have generally been modest. By combining these two modalities in a rationally designed first-in- human study, we propose to treat patients with a highly-defined T cell product (comprised of PRAME-specific memory T cells) in combination with an antigen- specific vaccine (comprised of a curated cocktail of synthetic long peptides) to augment and sustain the in vivo persistence of transferred PRAME-specific T cells. Addition of an immune checkpoint inhibitor, (anti-CTLA4), further favorably modulates the tumor environment by enabling un-fettered CD28 engagement of B7 (to expand the in vivo population of CD28-hi PRAME-specific memory T cells), lowering the threshold of activation of endogenous tumor-reactive T cells (facilitating antigen- spreading), and modulating inhibitory activity (by engaging CTLA4+ regulatory cells). This study, as proof of concept for this triple T cell-based strategy, will be used to address a critical unmet need for patients with metastatic uveal melanoma, and establish a versatile platform for targeting a broader range of tumor antigens and tumor types. In this study, all 3 modalities (PRAME vaccine, ETC therapy and anti-CTLA), are reduced to clinical practice and by using a highly-defined antigen-specific T cell population for adoptive therapy, allows for rigorous immunologic analysis so that reasons for success or failure can be elucidated. In an effort to enhance efficacy as well as broaden this approach to benefit a larger pool of patients, PRAME epitopes presented by additional HLA Class I and II alleles will be identified. The results of the proposed studies may lead to formal Phase II trials to assess true efficacy, development of a new treatment standard for refractory metastatic uveal melanoma, and refinement of CD4 T cell and combined CD4 and CD8 T cell strategies that can be incorporated into future clinical studies. This proposal leverages the clinically-tested expertise in therapeutic cancer vaccines at ISA Pharma and the pioneering development of ETC therapy in the Yee Lab to explore an opportunity that is timely and ideally suited for an academic – industrial partnership.