Enhancing CAR-T solid tumor efficacy with secretory iRGD

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Chimeric Antigen Receptor T-cell (CAR-T) therapy is a form of cancer immunotherapy that engineers T cells to recognize a specific tumor antigen and lyse the corresponding tumor cell. CAR-T therapy is rapidly evolving and has revolutionized the treatment of certain hematological malignancies. Its use against solid cancers such as pancreatic cancer, however, has limited success, largely due to the impenetrability of the immunosuppressive tumor microenvironment (TME). iRGD is a cyclic tumor-penetrating peptide that binds to αvβ3 and αvβ5 integrins, leading to its proteolytic cleavage and release of the C-terminal, RGD-containing CendR motif. Binding of the CendR motif to the cellular transport protein neuropilin-1 (NRP-1) triggers an increase in transcytosis, ECM remodeling, and vascular permeability, thus facilitating entry of therapeutic agents into the tumor. While iRGD has been combined with chemotherapy and select immunotherapies, here, we propose the unprecedented combination of the iRGD peptide with CAR-T therapy. Specifically, we utilize secretory iRGD (developed by our collaborators Sugahara et. al. at Columbia University) engineered into CAR- T cells as a novel delivery mechanism, in an effort to increase local iRGD surrounding infiltrating CAR-T cells. We hypothesize that iRGD CAR-T therapy will have greater anti-tumor efficacy in orthotopic and intraperitoneal xenograft and syngeneic models of pancreatic cancer compared to standard CAR-T therapy. Moreover, we expect that iRGD CAR-T therapy will contribute substantial remodeling of tumor microenvironment vasculature, stroma, and myeloid and lymphoid cell populations, and we will investigate these effects using spatial transcriptomics and single-cell RNA sequencing. Our preliminary data demonstrate proof-of-principle that 1) we can engineer iRGD-secreting CAR-T cells, which 2) retain equivalent in vitro cytotoxicity against target (pancreatic cancer) cells and 3) exhibit increased tumor infiltration into in vivo. Data also suggest a potential role for iRGD alone in inhibiting TGFβ activation, as well as reducing angiogenesis and stromal fibers in the pancreatic cancer TME. Our study, if successful, will contribute an innovative and translatable advancement to the treatment of solid tumors with CAR-T therapy.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Chimeric Antigen Receptor T-cell (CAR-T) therapy currently has limited efficacy against solid cancers, largely due to immunosuppression and impenetrability of the solid tumor microenvironment. Here, we engineer CAR-T cells to secrete iRGD, a tumor-targeting peptide that increases permeability of tumor tissues and vasculature. Our goal is to improve CAR-T cell infiltration into solid cancers and remodel the tumor microenvironment with iRGD, leading to better therapeutic efficacy.