BackgroundEffective therapies for PDAC are urgently needed. CAN-2409 is a replication-defective adenovirus encoding the HSV-thymidine kinase gene, administered intratumorally in combination with a prodrug (valacyclovir or acyclovir). Cells transduced with CAN-2409 activate prodrug, resulting in immunogenic cell death and release of tumor neoantigens within the inflammatory tumor microenvironment. Together, this results in in situ vaccination against the patient’s tumor. A phase 1 clinical trial in PDAC previously showed marked infiltration by CD8+ T cells and initial evidence of clinical activity after administration of CAN-2409+prodrug.MethodsPaTK02 is an open-label phase 2 clinical trial evaluating safety and efficacy of CAN-2409+prodrug combined with standard of care (SOC) chemoradiation (CR) and surgery for borderline resectable (BR) or locally advanced (LA) PDAC. Three courses of CAN-2409+prodrug were administered after induction chemotherapy, during CR, and during surgery. Primary endpoints include resection rate and overall survival (OS) rate (24 months). CA19–9 longitudinal changes were reported for treatment arm (n=9) and controls (n=9). Immune profiling of serial samples for 4 test arm patients and 3 controls was performed using OLINK.Results19 patients were enrolled by data cutoff (01MAY2023): 10 in test arm (7 BR, 3 LA) and 9 in control arm (6 BR, 3 LA). 3 BR patients and 1 LA patient were successfully resected in both test and control arms. Median OS was not reached in BR patients receiving CAN-2409 compared to 12.5 mo amongst controls; OS24 was estimated as 62.5% in CAN-2409 vs. 16.7% in control patients (figure 1). Mortality was comparable by arm in LA patients. No dose-limiting toxicities were reported, including no cases of pancreatitis. Most adverse events were grade 1 and 2; common related events were nausea and fatigue (n=4 each). CAN-2409 treatment was associated with lower CA19–9 trajectory in post-treatment samples (figure 2). We observed, in test arm patients, an increase in levels of soluble granzymes B and H (respectively, 21% and 14% increase vs. 0% and 8% decrease in control arm). IL-10 increased by 11% for test arm patients and decreased by 5% in control patients, while IFNγ increased by 19% in test patients, but only 8% in control patients.ConclusionsIn patients undergoing SOC treatment for PDAC, treatment with CAN-2409+prodrug was well tolerated and associated with increased OS in BR patients. CAN-2409+prodrug reduced CA19–9 levels, suggesting an effect on tumor volume consistent with CAN-2409’s mechanism of action. Biomarker analysis demonstrated systemic activation of the immune response.Abstract 653 Figure 1OS in borderline resectable PDAC by treatment arm, time from enrollmentAbstract 653 Figure 2CA 19–9 trajectory by treatment arm