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Title

Next generation T cell therapies for mutant KRAS solid tumors

Principal Investigators

Dr. Beatriz M. Carreno
Dr. Gerald P. Linette
Dr. Carl June

Description

A critical limitation in the development of new adoptive cell therapies (ACT) is the paucity of high-quality tumor antigens. Our group has been investigating mutant KRAS (Kirsten rat sarcoma virus, mKRAS), detected in ~20-25% of all malignancies, as a tumor antigen. The majority of KRAS genomic alterations are missense mutations which occur at codon 12 and the most frequent KRAS variants are G12D, G12V, and G12C which create neoantigens restricted to MHC-I and MHC-II molecules. mKRAS is an attractive target for several reasons: (1) it is clonal driver oncoprotein promoting cell growth and proliferation, (2) the expression is restricted to pre-malignant lesions and tumors, (3) small molecule inhibitors show potent clinical activity in lung cancer clinical trials and (4) case reports of ACT targeting G12D/HLA-C08:02 demonstrate clinical activity. Our recent work has focused on implementation of new gene editing strategies to optimize effector cell potency and safety of T cell products. Of relevance to this application, is a T cell receptor (TCR) specific for mKRAS G12V in the context of HLA-A11:01, namely TCR1020. Given the cost and regulatory considerations of manufacturing cell products for clinical trials, we propose that base editing (BE) offers important advantages over current gene-editing platforms, especially for early proof-of-concept studies enabling rapid translation to the clinic. In addition, augmenting persistence and potency while optimizing safety of engineered cell products is also essential to ensure clinical success. Finally, investigators must surmount the unique barriers imposed by the solid tumor microenvironment to promote T cell infiltration and effector function. Based on these observations, we hypothesize that targeting mKRAS thru the action of TCR1020-T cells, engineered to overcome cell intrinsic mechanism 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 first-in-human phase 1 study.
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.