Ad5.F35-GUCY2C-PADRE (GUCY2C-directed adenoviral vaccine) drives dose-dependent T-cell immunity and signals improved 2-year RFS in resected CRC

Ad5.F35-GUCY2C-PADRE is an off-the-shelf chimeric Ad5/35 vector vaccine targeting the intestinal tumor antigen GUCY2C and incorporating PADRE to enhance CD4+ help, designed to bypass pre-existing anti-Ad5 neutralizing antibodies. In this open-label Phase 2A dose-finding study (NCT04111172) in resected high-risk GI adenocarcinomas with no evidence of disease post-adjuvant therapy (46 evaluable; CRC n=29; includes oligometastatic stage IV CRC n=8), three IM vaccinations q4w were given at 1×10^11, 1×10^12, or 5×10^12 viral particles; GUCY2C-specific ELISpot responses at 4 weeks post–dose 1 rose with dose (33%→94%→100% responders; p<0.0001) with higher-dose responses largely independent of baseline NAb status. Safety was benign (no DLTs, no TRSAEs; mostly grade 1–2 flu-like AEs), and among stage II–III CRC (excluding stage IV), recurrence rates at ~2 years numerically improved with dose (50% [4/8] at 1×10^11 vs 17% [1/6] at 1×10^12 vs 0% [0/7] at 5×10^12; p=0.051) with “median RFS not reached” at the two higher doses; immune responders also had significantly better RFS than non-responders (p<0.05). Versus current post-resection standard (surveillance after completion of adjuvant fluoropyrimidine/oxaliplatin where appropriate), this looks directionally better than the typical ~75% 3-year DFS seen in large Stage III adjuvant datasets—though this trial is small, noncomparative, and enriched for immunologic endpoints.