Pancreatic adenocarcinoma (PDAC) represents one of the most lethal Hard-To-Treat Cancers, accounting for more than 90% of pancreatic malignancies and being predicted to become the second leading cause of cancer-related death by 2030. To address such a cogent unmet medical need, CAR4PDAC project plans the delivery of a novel and alternative therapeutic approach based on the targeting of the fibronectin/integrin axis by Chimeric Antigen Receptor (CAR)-T cells. Such strategy is expected to overrule the contribution of fibronectin, its extradomain A (EDA) spliced version, and of integrins to tumor growth, migration, invasion and to the reorganization of the tumor extracellular matrix and intratumor immunosuppression. Our preliminary data indicate that CAR-T cells targeting EDA show antitumor effect in several tumor models expressing EDA in the tumor extracellular matrix, and that EDA is highly expressed in PDAC tumor stroma. Moreover, an anti-avb6/avb8 dual targeting CAR-T can recognize mouse and human PDAC in vitro and in vivo. Thus, evidence produced by the CAR4PDAC consortium indicate that EDA and avb6/avb8 integrins represent potential novel CAR-T cell targets for PDAC treatment.
Combining relevant mouse models, patient-derived organoids and state-of-the-art genomic technologies, the specific objectives foresee:
1) the preclinical validation of EDA and avb6/avb8 integrins as antigens in PDAC samples of available biobanks and human organoids.
2) their targeting by CAR-T cells against PDAC in mouse models, patient-derived xenografts and human organoids.
3) understanding the molecular mechanism behind CAR-T function.
4) the delivery of CAR-T manufacturing under GMP conditions and the accrual of data for the compilation of an IMPD.
Expected results should impact the management of PDAC patients lacking therapeutic options, by the delivery of proprietary tools suitable for clinical and commercial development by existing European enterprises and medical centers.