Neoadjuvant and adjuvant antitumor vaccination alone or combination with PD1 blockade and CD137 agonism in patients with resectable pancreatic adenocarcinoma.
Authors: Heumann Thatcher Ross , Judkins Carol , Lim Su Jin , Wang Hao , Parkinson Rose , Gai Jessica , Celiker Betul , Durham Jennifer N. , Laheru Daniel A. , De Jesus-Acosta Ana , Le Dung T. , Narang Amol , Anders Robert A , Soares Kevin , Burkhart Richard A. , Burns William , Thompson Elizabeth , He Jin , Jaffee Elizabeth M. , Zheng Lei 
Published: January 2022

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Background: Utilizing a vaccine that induces and activates host effector T cells and co-administering it with immune modulating agents that enhance anti-tumor T cell activity is a potential strategy for overcoming pancreatic adenocarcinoma’s (PDA) resistance to immunotherapy. Our prior clinical trial demonstrated a GM-CSF-secreting, allogeneic tumor cell vaccine (GVAX) increases infiltrating CD8+ T cells in PDA. Follow up preclinical work demonstrated therapeutic synergy between GVAX and PD-1inhibition (PD1) with efficacy further enhanced by CD137 agonism (CD137). Methods: This was a 3-arm trial of neoadjuvant & adjuvant GVAX-based therapy in resectable (r) PDA patients (pts). Adults with clinically resectable, untreated PDA were enrolled in 1 of 3 study treatments: Arm A (GVAX alone), Arm B (GVAX + PD1 [Nivolumab]), or arm C (GVAX + PD1 + CD137 [Urelumab]). Treatment was given as follows: Day 1 - Cyclophosphamide 200mg/m2 IV (All Arms), Nivolumab 480mg IV (Arms B, C), Urelumab 8mg IV (Arm C); Day 2 – GVAX ID (All Arms). Pts were treated at 3 timepoints: 1) once 2 weeks prior to surgery; 2) once post-surgical recovery prior to standard of care adjuvant chemotherapy (SOC); 3) every month (up to 4 mo) following completion of SOC (if disease-free). SOC regimes included (m)FOLFIRINOX, Gem +/- Cap/NAB-Paclitaxel. The study was powered for a primary biologic endpoint: treatment-related change in intratumoral CD8+CD137+ T cells. Clinical endpoints included disease-free survival (DFS: time from surgery to recurrence), overall survival (OS: time from surgery to death), and safety. Results: 38 pts (N = 15 [Arm A], N = 13 [Arm B], N = 10 [Arm C]) were eligible for efficacy analysis (had R0/R1 resection) and 45 pts (N = 17 [A], N = 17 [B], N = 11 [C]) were eligible for safety analysis (had ≥1 dose of study treatment). Demographics, surgical pathology features, and SOC durations were similar in all Arms. At median follow up of 23 mo [A], 26 mo [B], and 22 mo [C], median DFS (95% CI) was 14.82 mo (6.0, NA), 16.23 mo (7.49, NA) and not reached (16.33, NA) for Arms A, B, C, respectively. There was no DFS benefit to adding PD1 compared to GVAX alone (HR 0.98 [95% CI 0.42, 2.27], p = 0.96). Combination CD137 + PD1 + GVAX was associated with marginally significant improved DFS compared to GVAX alone (HR 0.38 [95%CI 0.12, 1.19], p = 0.097) and GVAX + PD1 (HR 0.38 [95%CI 0.12, 1.21], p = 0.103). Median OS (95% CI) was 25.0 mo (18.8, NA), 26.4 mo (20.3, NA), and not yet reached for Arms A, B, C, respectively. There were no serious adverse events. In Arm C, 1 pt had grade 3 rash that delayed treatment and there was 1 instance of grade 2 AST/ALT elevation. The biologic endpoint will be reported at the meeting. Conclusions: Despite a small sample size, combining GVAX with dual immune-targeting of PD-1 blockade and CD137 agonism was safe and may enhance DFS in rPDA pts treated in the perioperative and post-adjuvant settings. Clinical trial information: NCT02451982.