Despite therapeutic advances outcomes are still poor for patients with most relapsed/refractory malignancies. Recently CAR-T cell therapies have demonstrated significant potential to markedly improve the outcomes of patients with relapsed refractory B cell and plasma cell malignancies. Unfortunately to date, CAR-T cells have not demonstrated similar efficacy for patients with solid tumors or other blood cancers. A major challenge for the development of CAR-T cells for these malignancies is the paucity of targets on cancer cells that do not exhibit cell surface expression on normal cells leading to significant toxicities that can correlate with efficacy. We recently identified the non-classical MHC molecule, MR1, is a promising target for CAR-T cells. MR1 is typically found in the cytoplasm in the vast majority of cells and was recently reported to traffic to the cell surface in a wide variety of tumor cells when bound to cancer cell specific metabolites. We validated the cell surface specific expression of MR1 protein in a wide range of malignancies including pancreatic, prostate, brain, melanoma, breast, lung and AML. Further we developed a CAR-T cell product that utilizes a non-traditional CAR design to enable it to be efficacious against the low levels of cell MR1 found on the surface of tumor cells. Pilot mouse tumor studies demonstrate the potential safety and efficacy of this approach. In this proposal we will focus on the development of MR1 CAR-T cells for a blood cancer, AML, and a solid tumor, glioblastoma, that both urgently need new therapeutic options. Here we will 1) Assess the cell surface expression of MR1 in primary patient AML and glioblastoma samples and normal controls 2) Perform mouse efficacy studies using AML and glioblastoma models and 3) Assess the safety of MR1 CAR-T cells using mouse and in vitro models. It is hoped that this work will lead to an MR1 CAR-T cell product that can improve the outcomes of patients with cancer.