Ad5.F35-GUCY2C-PADRE (adenoviral vaccine swapping Ad35 fiber) drives CD8+ immunity and fewer CRC recurrences

Ad5.F35-GUCY2C-PADRE is a chimeric adenovirus serotype 5 vaccine expressing the intestinal tumor antigen GUCY2C (plus PADRE helper epitope) and using an Ad35 fiber to bypass pre-existing anti-Ad5 neutralizing antibodies. In this open-label Phase 2A dose-finding trial in resected, high-risk GI cancers post–standard adjuvant therapy (NCT04111172), disease-free patients 4–24 weeks after treatment were randomized to 3 IM doses (q4w) at 1×10^11 (DL1), 1×10^12 (DL2), or 5×10^12 (DL3) viral particles; 46 patients were evaluable (29 CRC, 16 PDAC, 1 gastric), with primary endpoints of safety and GUCY2C-specific T-cell responses by IFNγ ELISpot. No DLTs or treatment-related severe AEs were reported (mostly grade 1–2 flu-like symptoms), and GUCY2C-specific T-cell responses increased dose-dependently, were CD8+ dominant, and at DL3 occurred in 100% of patients regardless of baseline NAb status; clinically, PDAC evaluation was limited by target prevalence (GUCY2C IHC+ in 25% of PDAC vs 100% of CRC), so the recurrence signal was assessed in stage II–III CRC, where 2-year recurrence was 50% (DL1) vs 17% (DL2) vs 0% (DL3) (P=0.051) and immune responders had longer RFS than non-responders (median not reached vs 512 days; P=0.0475)—directionally better than typical post-resection stage II–III CRC recurrence risk, which remains substantial even with modern adjuvant chemo and is front-loaded in the first ~2 years.