Development of an In-House KRAS Specific TCR-T Platform for Pancreatic Cancer Patients at Sheba Medical Center

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies and is largely refractory to current therapies. As approximately 90% of PDAC tumors harbor KRAS mutations, mutant KRAS is an attractive target for T-cell receptor (TCR)-based immunotherapy. We recently initiated a clinical trial at Sheba Medical Center using KRAS-specific TCR-engineered T cells, supported by an integrated translational platform in which retroviral vector production is performed at the Advanced Biotherapy Center and cell manufacturing at the Ella Institute. This in-house infrastructure enables rapid translation from TCR discovery to clinical treatment.

To date, two patients with PDAC have been treated. We present immunological and clinical data from one patient who developed three liver metastases after pancreatic resection. Following infusion of KRAS-specific T cells, peripheral blood analyses demonstrated inflammatory activation and an early reduction in circulating tumor markers. A murine-derived TCR constant region enabled tracking of infused cells, which comprised 25% of circulating T cells on day 3 and remained detectable for up to 8 months. CyTOF analysis showed sustained activation and persistence of an effector-memory phenotype in infused CD8 T cells. Multiplex imaging also identified infused T cells in ascites, supporting trafficking to disease sites.

Clinically, two liver metastases resolved after treatment, whereas a third lesion progressed. These findings demonstrate the therapeutic potential of KRAS-specific TCR-T cells, while highlighting the biological challenges of treating solid tumors. Overall, this work establishes the feasibility of a fully integrated in-house TCR-T platform at Sheba for next-generation personalized cellular immunotherapy.