Disrupting TIGIT by cytosine base editing enables effective and safe T-cell therapy for pancreatic cancer [WES]

Pancreatic ductal adenocarcinoma (PDAC) is a severe disease with limited treatment options. While adoptive cell therapy (ACT) has revolutionized hematological malignancy treatment, it mediated suboptimal results in solid tumors, including PDAC. Here, we isolated 5 TCRs targeting tumor-associated antigens expressed by PDAC and employed cytosine base editing to edit T-cell specificity. We additionally knocked-out TIGIT, a key immunosuppressive molecule in PDAC, to enhance the potency of our cellular products. While producing marginal benefits on high-avidity T lymphocytes, TIGIT knockout enabled low-avidity T cells to control tumor outgrowth in vivo by fostering the immunological synapse between T and cancer cells. Cytosine base editing for TCR-edited TIGIT knockout T cells avoided genotoxic DNA modifications, displaying an optimal safety profile. These results identify TIGIT disruption as a strategy to rescue low-avidity T cell functions widening the repertoire of exploitable TCRs to engineer T cells for the treatment of PDAC and other malignancies.