Long term results from a phase 1 trial of GEN-009, a personalized neoantigen vaccine, combined with PD-1 inhibition in advanced solid tumors.
Authors: Gillison Maura L. , Awad Mark M. , Twardowski Przemyslaw , Sukari Ammar , Johnson Melissa Lynne , Stein Mark N. , Hernandez Richard , Price Jessica , Mancini Kevin J. , Shainheit Mara , Vemulapalli Vijetha , Flechtner Jessica , Davis Thomas A. , Cohen Roger B. 
Published: June 2021

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Background: GEN-009 is an adjuvanted personalized cancer vaccine containing up to 20 neoantigens selected by ATLAS, an ex vivo bioassay screening autologous T cells for immune responses against both neoantigens as well as Inhibigens. Inhibigen-specific T cells suppress immunity and have been shown to accelerate tumor progression in mice and are avoided in GEN-009. In cohort A, all patients immunized in the adjuvant setting with GEN-009 monotherapy developed immune responses. Nearly all (99%) of selected peptides were immunogenic: ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides, respectively. Seven of 8 patients continue without progression with a median follow up of 18 months. Methods: GEN-009 is being evaluated in patients (pts) with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing. Five vaccine doses were administered over 24 weeks in combination with a PD-1 CPI. Patients who progressed prior to vaccination received alternative salvage therapy followed by GEN-009 in combination. Peripheral T cell responses were measured by fluorospot assays in ex vivo and in vitro stimulation. Results: 15 pts received GEN-009 in combination with a PD-1 inhibitor; 1 patient received GEN-009 monotherapy. Median number of neoantigens per vaccine was 14 (5-18). GEN-009-related adverse events were limited to vaccine injection site reactions and mild myalgias or fatigue. Longitudinal evaluation of ex vivo T cell responses revealed that sequential vaccination with GEN-009 had an overall additive effect on the robustness of IFNγ secretion and responses were persistent for at least 6 months in some patients. Epitope spread was detected in CPI sensitive patients, but not in CPI refractory patients receiving salvage therapy. Three patients who responded to PD-1 inhibition followed by disease stabilization then demonstrated further reduction after GEN-009 vaccination that could represent vaccine effect. Eight of 9 CPI responsive patients are progression-free from 3 to 10 months after first vaccine dose. Four of 7 CPI refractory patients have experienced unexpected prolonged stable disease after vaccination of up to 8 months after vaccination. 2 of 2 patients with available samples lost all evidence of circulating tumor DNA including non-targeted neoantigens. Conclusions: Vaccination with GEN-009 in combination with anti-PD-1 CPI in patients with advanced solid tumors shows little additive toxicity. Preliminary data demonstrate induction of broad neoantigen-specific immune responses and epitope spreading in the presence of PD-1 CPI. Broad immunity against tumor specific targets and encouraging patient outcomes support further study. Clinical trial information: NCT03633110.