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Cited by 33Pancreatic and Hepatic Oncology ResearchImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

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

Balachandran, Vinod P., Rojas, Luis A., Sethna, Zachary, Soares, Kevin, Derhovanessian, Evelyna, Mueller, Felicitas, Yadav, Mahesh, Basturk, Olca +12 more·2022·Journal of Clinical Oncology
DOI 10.1200/jco.2022.40.16_suppl.2516
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Abstract

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]

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  • In advanced PDAC trials, hyaluronic acid-targeted therapies were given at doses roughly a thousandfold lower than those that improved survival in animal models.

    “An unfortunate example of this pertains to the trials of hyaluronic acid targeted therapies in patients with advanced PADC, which used dosages that were three orders of magnitude lower than what garnered improved survival in animal models291.”

    From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [291]

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Authors
Balachandran, V. P., Rojas, L. A., Sethna, Z., Soares, K., Derhovanessian, E., Mueller, F., Yadav, M., Basturk, O., Gonen, M., Wei, A. C.-C., D'Angelica, M. I., Kingham, T. P., Greenbaum, B., Merghoub, T., Jarnagin, W. R., Drebin, J. A., Sahin, U., Tuereci, O., Wolchok, J. D., & O'Reilly, E. M.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • BioNTech (Germany) (DE)
  • Genentech (US)
  • Memorial Sloan Kettering Cancer Center, New York, NY;
  • BioNTech SE, Mainz, Germany;
ORCID
Venue
Journal of Clinical Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2022-06-01
Volume
40
Issue
16_suppl
Pages
2516-2516
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
DOI
10.1200/jco.2022.40.16_suppl.2516
OpenAlex
W4286293094
Cited by
33
References
0
Citations by year
2026: 4 · 2025: 5 · 2024: 9 · 2023: 14 · 2022: 1
Type
conference abstract
Language
en
Open access
closed
Locations
Journal of Clinical Oncology (publishedVersion)
Funders
  • Genentech Inc, BioNTech
  • Other Foundation.
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
pancreatic ductal adenocarcinoma, mRNA vaccines, adjuvant immunotherapy, atezolizumab, FOLFIRINOX, tumor immune microenvironment, immune exclusion, vaccine safety, recurrence-free survival, IFN-gamma ELISPOT, T cell clonal expansion, neoantigen discovery

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