CAR-based treatments for PDAC: from the identification of promising antigens to the development of novel CAR immune cells

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly malignant cancer with limited treatment options. It evades the host immune surveillance by manipulating immune cells to establish an immunosuppressive microenvironment (TME). Therefore, although immunotherapy has emerged in recent years as a potentially effective treatment in some type of cancers, it still remains a hope for PDAC. In this thesis, I’ll discuss three papers that demonstrate how genetically engineered T cells to express Chimeric Antigen Receptors (CARs) could be considered a novel immunotherapeutic tool even for PDAC treatment. The first article exploits the overexpression of the transmembrane glycoprotein CD47 by multiple cancer types for the design of a novel second-generation CAR-T cell construct. CD47-CAR-T cells effectively killed multiple cancer cell lines, in vitro, among which also the pancreatic BxPC1. In addition, they reduced BxPC3 pancreatic xenograft tumor growth when injected intratumorally. In the second study, authors designed a third-generation CAR construct targeting the Programmed Death 1 (PD-1)/ Programmed Death Ligand 1 (PD-L1) immune checkpoint. It is, in fact, known that cancer cells overexpress PD-L1 to induce T cell exhaustion. Indeed, anti-PDL1 CAR-T cells eliminated about 80% of PD-L1-over-expressing pancreatic CFPAC1 cells, in vitro, and induced a specific regression of more than 80% of established CFPAC1 cancer in both xenograft and orthotopic models. The last paper demonstrates innovative CAR-engineered immune cells which are macrophages, as believed a better tool to overcome some CAR-T cell limits: one for all, their inability to properly infiltrate tumor tissues. Thus, macrophages were engineered to express chimeric tumour-associated antigen (TAA) receptors. These CAR-Macrophages (CAR-M) exhibited a tumor antigen-specific phagocytosis, in vitro, and were able to induce a decreased tumor burden paralleled by an increased survival when injected in xenograft mouse models. Moreover, the cytokine secreted by CAR-Ms affected the TME by shifting Tumor Associated Macrophage (TAMs) phenotype from a pro-tumoral M2 to a pro-inflammatory M1. Lastly, the authors proved that CAR-Ms were able to potentiate a nonspecific, allogeneic T cell anti-tumor activity. Overall, these papers highlight new promising antigens and approaches to target PDAC cells and elicit an anti-tumor immune response to improve cancer treatment.