Next generation T cell therapies for mutant KRAS solid tumors

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Project Summary This proposal “Next generation T cell therapies for KRAS mutated solid tumors” was developed in response to RFA-CA-22-028 and to fulfill the Cancer Adoptive Cellular Therapy Network (Can-ACT) objectives. The focus of our proposal is targeting mutant KRAS, a clonal driver oncoprotein, by the early-stage clinical testing of TCR1020, a T cell receptor specific for mKRAS G12V restricted to HLA-A*11:01. If successful, this novel-state- of-the-art Adoptive Cell Therapy (ACT) could be available to ~5,000 new solid tumor patients per year in the US. Advances in gene editing together with new insights related to mechanisms of T cell exhaustion provide the scientific basis for development of the next generation T cell therapies in solid tumors. Our central hypothesis is that targeting mutant KRAS through the action of TCR1020-T cells, engineered to overcome cell intrinsic mechanisms of exhaustion and counteract a cell extrinsic myeloid checkpoint to overcome TME resistance, will promote durable tumor regression in solid tumors. There are three hypothesis-driven specific Aims in this proposal. In Aim 1, we will develop genetically modified T cells expressing TCR1020 targeting mKRAS G12V/HLA-A*11:01 to overcome extrinsic and intrinsic mechanisms of resistance. In Aim 2, we plan to evaluate TCR1020-T CD4+ cells to improve the persistence and potency of mKRAS specific CD8+ effector cells. In Aim 3, the safety and clinical activity of engineered TCR1020-T cell products will be determined in a dose escalation multi-site phase 1 study. We have assembled an exceptional group of investigators with an extensive track record of collaboration and productivity with expertise in human immunology, immuno-oncology, cell therapy, T cell engineering and gene editing. Additionally, experts in molecular pathology and biomarker discovery will contribute to cutting-edge correlative studies to aid in biomarker development and TME characterization to delineate potential mechanisms of response and resistance. The Center for Cellular Immunotherapies (CCI) at the University of Pennsylvania has extensive expertise in the development of ACT therapies producing more than 2,500 cell products for administration to adult and pediatric patients. CCI has a long track record of technology transfer related to cell therapies to both large pharmaceutical companies (Novartis, Kymriah) and biotechnology companies over the past decade. As a multi-site trial application, an important programmatic component of our proposal is to leverage NCI resources thru utilization of the Immune Cell Network (ICN) Core at FNLCR to manufacture, test, release and distribute the engineered TCR1020-T cell products. In summary, our proposal incorporates multiple scientific and technological innovations that targets a recurrent clonal driver oncoprotein with engineered T cells modified to resist T cell exhaustion and overcome the immunosuppressive TME.