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Potentiating CAR T cells infiltration and functionality in solid tumors by modulation of integrins


The clinical treatment of several hematological tumors has been revolutionized by chimeric antigen receptors T cells (CAR T) targeting antigens expressed at the surface of tumor cells to eradicate them. However, its performance is still below expectations against solid tumors, mainly due to the inefficient migration and transit of CAR T cells in these tumor sites and the frequent local immunosuppression that limits the cytotoxic activity of T cells. Several hypoxic tumors and, constitutively, the clear cell renal cell carcinoma (ccRCC) express high amounts of an enzyme called carbonic anhydrase IX (CAIX), which is considered a promising target for CAR T cells. This project presents two integrated aims, the first being the evaluation of antitumor effects of CAIX-targeted CAR T cells containing CD28 or 4-1BB as costimulatory domains in a ccRCC patient-derived xenograft model (PDX) and triple-negative breast cancer in NSG mice, evaluating their survival. The second aim consists of adapting the most efficient Anti-CAIX CAR T cells to co-express integrin modulators in the second cassette of the same Anti-CAIX CAR lentivector, through molecular cloning, aiming an enhanced T cell migration through the vascular endothelium toward the tumor. These integrin modulators can induce cytoskeletal remodeling, culminating in T cell adhesion and transendothelial migration. The lentiviruses will be produced by transient transfection, concentrated, titrated, and transduced into T cells purified from the blood of healthy donors. The resulting CAR T cells will be expanded, and their transduction levels will be accessed. The Anti-CAIX CAR T cells CD28 and 4-1BB will be evaluated in vitro and in vivo in a triple-negative breast cancer orthotopic model and ccRCC PDX model in NSG mice, determining their survival and the exhaustion status of tumor-infiltrating T cells. The Anti-CAIX CAR T cells expressing the integrin modulators will be tested in vitro for transendothelial migration, and cytotoxicity of ccRCC cells and in vivo in an orthotopic model of human ccRCC in NSG, determining the activation status of tumor-infiltrating CAR T cells. This project can potentially solve one of the main challenges of CAR T therapy against solid tumors, boosting the infiltration and optimizing the performance of CAR T cells in the tumor microenvironment. (AU)

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