Phase 1 Ad5.F35-hGUCY2C-PADRE + Lm-GUCY2C vaccines, GUCY2C-targeted T-cell immunotherapy

This open-label, non-randomized Phase 1 dose-escalation study at Thomas Jefferson University tests a heterologous prime-boost cancer vaccine strategy targeting GUCY2C, an intestinal lineage antigen commonly retained in colorectal cancer and small bowel adenocarcinoma metastases. The prime is Ad5.F35-hGUCY2C-PADRE, a chimeric Ad5/Ad35 fiber adenoviral vector encoding human GUCY2C plus the PADRE helper epitope to drive GUCY2C-specific T-cell responses. The boost is Lm-GUCY2C, an attenuated recombinant Listeria monocytogenes vector engineered to deliver GUCY2C antigen and amplify cellular immunity. Patients with advanced/metastatic colorectal adenocarcinoma or small bowel adenocarcinoma (including MSI-H/dMMR and MSS) who have progressed on available standard therapies receive a single IM prime, then two IV boosts 4 weeks apart across escalating Listeria dose levels; the primary aim is MTD/safety with immune readouts as key pharmacodynamic signals. Today’s care for refractory metastatic CRC/SBA is sequential systemic therapy (fluoropyrimidine/oxaliplatin/irinotecan backbones with biologics such as anti-VEGF and, when RAS wild-type, anti-EGFR; MSI-H/dMMR tumors often receive PD-1–based immunotherapy), and this program explores whether a GUCY2C-directed prime-boost can generate actionable anti-tumor immunity where checkpoint blockade is limited (especially in MSS disease).