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Phase I trial of adjuvant autogene cevumeran, an individualized mRNA neoantigen vaccine, for pancreatic ductal adenocarcinoma.

2022; Lippincott Williams & Wilkins; Volume: 40; Issue: 16_suppl Linguagem: Inglês

10.1200/jco.2022.40.16_suppl.2516

1527-7755

Vinod P. Balachandran, Luis A. Rojas, Zachary Sethna, Kevin C. Soares, Evelyna Derhovanessian, Felicitas Mueller, Mahesh Yadav, Olca Baştürk, Mithat Gönen, Alice C. Wei, Michael I. D’Angelica, T. Peter Kingham, Benjamin Greenbaum, Taha Merghoub, William R. Jarnagin, Jeffrey A. Drebin, Uğur Şahin, Oezlem Tuereci, Jedd D. Wolchok, Eileen M. O’Reilly,

Monoclonal and Polyclonal Antibodies Research

2516 Background: Pancreas ductal adenocarcinoma (PDAC) is a lethal cancer that claims ̃90% of patients in <24 months of diagnosis. PDAC is also refractory to immunotherapy as most tumors exhibit an immune excluded/desert phenotype. However, although characterized by low mutation rates, most PDACs harbor mutations that can generate immunogenic neoantigens. Here, we report the results of a phase-I trial of autogene cevumeran, a systemic RNA-lipoplex individualized neoantigen-specific immunotherapy (iNeST) vaccine, to stimulate immunity against neoantigens in resected PDAC patients. Methods: We conducted an investigator-initiated, single-center, phase-I trial of adjuvant autogene cevumeran containing up to 20 neoantigens in each individualized vaccine, identified from resected PDACs using real-time next generation sequencing and bioinformatic neoantigen discovery. Following surgery, patients received atezolizumab (1 dose; week 6), autogene cevumeran (8 weekly doses starting week 9; doses 9,10 – weeks 17, 46), and modified (m) FOLFIRINOX (12 cycles; starting week 21). Primary endpoint: safety. Other endpoints: feasibility (actual vs. target treatment time), vaccine response (responder = positivity by two independent blood assays: IFNg ELISpot and T cell clonal expansion), and recurrence-free survival (RFS). Target accrual: n=20. Results: n=19 patients underwent surgery and received atezolizumab at 6.3 weeks (median; 95% CI 6.0–6.57) after surgery with no ≥ grade 3 (Gr3) adverse events. n=16/19 patients (84%) received autogene cevumeran at 9.4 weeks (median; 95% CI 9–10) after surgery. n=1/19 (5%) had insufficient neoantigens for vaccine manufacture. n=1/16 (6%) developed a vaccine-related Gr3 fever and hypertension. n=15/16 vaccinated patients (94%) received mFOLFIRINOX (median 12 cycles; 95% CI 7–12). Autogene cevumeran expanded polyclonal (median 7.5 clones, 95% CI 2–28), IFNg-producing neoantigen-specific CD8 + T cells in 50% (n=8/16) of patients from undetectable levels to large fractions (median 2.9%, Table) of all blood T cells. At an early median follow-up of 15 months, vaccine responders (n=8) had a longer RFS vs. non-responders (n=8) (median not reached vs. 13.7 months, HR 0.08, 95% CI 0.01-0.5, P = 0.007). Conclusions: Autogene cevumeran is safe, feasibly manufactured in a clinically relevant timeframe, and immunogenic in PDAC. Vaccine induced neoantigen-specific immunity preliminarily correlates with improved PDAC outcome. Further clinical trials in PDAC are warranted. (This imCORE Network project was funded by Genentech Inc and BioNTech; additional funding from Stand Up To Cancer, Lustgarten Foundation). Clinical trial information: NCT04161755. [Table: see text]