Mutant KRAS peptide-based vaccine in patients at high risk of developing pancreatic cancer: Preliminary analysis from a phase I study
CANCER RESEARCH(2024)
Abstract
Abstract Background: The development of pancreatic ductal adenocarcinoma (PDAC) from the first driver event takes >10 years, providing a unique window of opportunity for early interception. As a frequent alteration identified in both PDAC and pancreatic premalignancy, mutant KRAS (mKRAS) has emerged as a potential target for immune-based interception strategies in individuals at high risk of developing pancreatic cancer. Methods: This is a single-arm, open-label, second-in-human phase I study of a pooled synthetic long peptide (SLP) vaccine with poly-ICLC adjuvant targeting up to six mKRAS subtypes (G12D, G12R, G12V, G12A, G12C, G13D) in patients with hereditary predisposition to developing PDAC (NCT05013216). Key inclusion: radiographic evidence of a pancreatic abnormality and eligibility under at least one of three high-risk groups based on family history of PDAC and/or germline mutation status. Vaccination schema: mKRAS vaccine given on weeks 1, 3, 5, and 13. Peripheral blood collected at baseline and weeks 5, 13, and 17 for analysis of immunogenicity by IFN-gamma ELISpot. Co-primary endpoints: safety and mKRAS-specific T cell response. Results: At the time of data cutoff (November 15, 2023), 15 out of 20 planned patients were vaccinated on study and evaluable for immunogenicity. All 15 patients achieved a mKRAS-specific T cell response, defined by the maximal fold change in the pooled average IFN-gamma-producing mKRAS-specific T cell density within 17 weeks post-vaccination (median: 12.3, range: 3.1-167). Differential immunogenicity elicited by individual mKRAS epitopes was noted in this cohort. Specifically, the mKRAS G12V peptide induced the highest fold change increase in antigen-specific T cell expansion (median: 32.6, range: 2.9-243) while the mKRAS G12D peptide was the least immunogenic (median: 7.6, range: 0.4-104). Regarding safety, all adverse events were grade 1 or grade 2 in severity per NCI CTCAE v5.0. The most frequent vaccine-related adverse events were injection site reactions (93.8%), fatigue (62.5%), chills (43.8%), and headache (37.5%). No safety signals were observed. Conclusions: For the first time, we demonstrate mKRAS-specific T cell responses induced by vaccination in a cohort of high-risk individuals with inherited predisposition to PDAC. These findings directly serve as proof-of-concept to advance vaccine strategies focused on intercepting the development of pancreatic cancer in high-risk populations. Support: Stand Up To Cancer, Lustgarten Foundation, and NIH/NCI. Citation Format: Saurav D. Haldar, Amanda Huff, Elizabeth Abou Diwan, Anna Ferguson, Carol Judkins, Jiayun Lu, Hao Wang, Hassan Sinan, Christopher Thoburn, Katherine M. Bever, Mark Yarchoan, Amy M. Thomas, Julie M. Nauroth, Daniel A. Laheru, Michael G. Goggins, Elizabeth M. Jaffee, Nilofer S. Azad, Neeha Zaidi. Mutant KRAS peptide-based vaccine in patients at high risk of developing pancreatic cancer: Preliminary analysis from a phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT022.
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