Safety, immunogenicity, and efficacy of Ad5.F35-GUCY2C-PADRE vaccine in patients with GI cancers at high risk of relapse: Results from a phase 2A trial.

3617 Background: Guanylyl cyclase C (GUCY2C) is an intestinal tumor antigen ectopically expressed in some gastroesophageal and pancreatic cancers, highly expressed in nearly all colorectal cancers (CRC), and retained in metastases. Adenovirus serotype 5 (Ad5)-based cancer vaccines, including those targeting GUCY2C, are limited by pre-existing neutralizing antibodies (NAbs) targeting Ad5. Ad5.F35-GUCY2C-PADRE is a chimeric Ad5 vector (fiber of serotype 35) developed to overcome anti-Ad5 immunity and induce durable antitumor T-cell responses. We report initial immunogenicity, safety, and recurrence outcomes from a phase 2A dose-finding study in patients with resected GI malignancies. Methods: This open-label phase 2A study enrolled patients with resected, high-risk GI adenocarcinomas (CRC, pancreatic, gastric, and small bowel) with no evidence of disease 4-24 wks after standard adjuvant therapies. Oligometastatic stage IV CRC patients were also allowed (n=8). Patients were randomized to receive three i.m. administrations of Ad5.F35-GUCY2C-PADRE at 1×10 11 , 1×10 12 , or 5×10 12 viral particles (vp) at 4-wk intervals. Primary endpoints were safety and GUCY2C-specific T-cell responses (IFNγ ELISpot). Exploratory endpoints included the impact of NAbs on T-cell responses and RFS, and the impact of dose on immunological and clinical outcomes. Results: Forty-six patients (29 CRC) completed treatment and were evaluable. Vaccination was well tolerated with no DLTs or TRSAEs; AEs were predominantly grade 1-2 flu-like symptoms. GUCY2C-specific T-cell responses increased in frequency and magnitude in a dose-dependent manner. Nearly all patients receiving higher doses produced T-cell responses regardless of NAb status (Table), supporting Ad5.F35 overcoming pre-existing NAbs. At the 2-year follow-up, there was a dose-dependent improvement in RFS among stage II-III CRC patients (Table), and RFS was significantly improved among immune responders vs non-responders ( P < 0.05). Conclusions: Ad5.F35-GUCY2C-PADRE is safe, overcomes pre-existing Ad5 immunity, and induces robust, dose-dependent GUCY2C-specific T-cell responses. Vaccine-induced immunity is associated with improved RFS in CRC, supporting further development of the off-the-shelf Ad5.F35 platform for cancer vaccines and Ad5.F35-GUCY2C-PADRE for CRC recurrence prevention. Clinical trial information: NCT04111172 . Dose (vp) Magnitude of GUCY2C-Specific T-cell Response 1 % of Patients with a GUCY2C-Specific T-cell Response (N/N) 2 CRC 3 Recurrences (%; N/N);Median RFS 1x10 11 9 33% (5/15) 50% (4/8); 512 days 1x10 12 92 94% (15/16) 17% (1/6); not reached 5x10 12 218 100% (15/15) 0% (0/7); not reached P < 0.0001 P < 0.0001 P = 0.051 1 Median SFCs/5×10 5 PBMCs ; 2 at 4 weeks after 1 st vaccination ; 3 excluding stage IV patients .