Development of novel C9 CAR-T cells for pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor with a global incidence <5/100k and unmet medical needs. It is typically diagnosed at an advanced stage, which limits surgical options and portends a poor prognosis. Various chemotherapy techniques, either alone or in combination, have demonstrated low efficacy and toxicity profiles in patients while delivering minor survival gains. Chimeric antigen receptor (CAR) T-cell immunotherapy has shown notable success in the treatment of haematological malignancies but its effectiveness in PDAC has been limited, largely due to the restricted repertoire of tumor antigens accessible for targeting. Moreover, most of the identified targets are shared with normal tissues, often causing on-tumor/off-target toxicity affecting the effectiveness of such therapies. This highlights the pressing need to identify novel and specific biomarkers for PDAC. In the current study, we accomplished this aim by investigating the potential role of oncofetal chondroitin sulfate (ofCS), a uniquely modified form of chondroitin sulfate (CS) as a novel and cancer-specific target, universally expressed on the membrane of various cancer cells including cancer stem cells and focused on developing an adoptive T-cell therapeutic approach against this antigen. We have shown that ofCS is universally expressed in a repertoire of primary PDAC lines as well as in circulating tumor cells assessed using flow cytometry and on human and murine PDAC tissues using immunofluorescence, while confirming the specificity of our novel antibody against this target. Third-generation indirect anti-ofCS CAR-T cells were generated from healthy donor mice spleens and their tumor-killing potential tested in a murine in-vitro setting. Our data demonstrated ofCS as a novel universal cancer-specific antigen that can be exploited as a target using murine CAR-T cells.