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Background: Novel strategies are needed to decrease the high recurrence rates of pancreatic ductal adenocarcinoma (PDAC) after curative-intent surgery. Mutant KRAS (mKRAS) is an oncogenic driver found in approximately 90% of PDAC that has emerged as a target for neoantigen-specific vaccination. Methods: This is a single-arm, open-label, first-in-human phase I study of a pooled synthetic long peptide (SLP) vaccine targeting six mKRAS subtypes (G12D, G12R, G12V, G12A, G12C, G13D) combined with ipilimumab/nivolumab (ipi/nivo) in patients with resected PDAC (NCT04117087). Key inclusion criteria: presence of a vaccine-targeted KRAS mutation, disease-free status after completing adjuvant chemotherapy within 6 months of enrollment. Priming phase: mKRAS vaccine given on days 1, 8, 15, and 22 along with ipi 1 mg/kg every 6 weeks for 2 doses and nivo 3 mg/kg every 3 weeks for 4 doses. Boost phase: mKRAS vaccine given on weeks 13, 21, 29, 37, and 45 along with nivo 480 mg every 4 weeks for 10 doses. Co-primary endpoints: safety, mKRAS-specific T cell response. Secondary endpoints: disease-free survival (DFS), overall survival (OS). Results: At the time of data cutoff (December 1, 2022), 11 patients were treated with a median follow-up time of 10.7 months. 8/11 patients achieved a mKRAS-specific T cell response, defined as >5-fold change in IFN-gamma-producing mKRAS-specific T cells within 17 weeks post-vaccination, as assessed by serial ELISpot. The median fold change in IFN-gamma-producing mKRAS-specific T cells within 17 weeks post-vaccination was 10.2 (range: 1.5-686.3). The majority of all adverse events were grade 1 (79.5%) or grade 2 (15.2%) in severity per NCI CTCAE v5.0. Four grade 3 immune-related adverse events (pneumonitis, adrenal insufficiency, arthralgias, myalgias) and discontinuation of checkpoint blockade occurred in 2/11 patients. The median DFS for the entire cohort was 6.4 months and not reached for OS. Patients who mounted a mKRAS-specific T cell response demonstrated a significant improvement in median DFS compared to immune non-responders (not reached vs 2.8 months, p = 0.045). Conclusions: The combination of a pooled SLP mKRAS vaccine and dual checkpoint blockade is tolerable and immunogenic in patients with resected PDAC. Induction of an mKRAS-specific T cell response is associated with improved DFS in this cohort. Ongoing correlative studies will apply multi-omic approaches to identify novel biomarkers of immune response and resistance. Citation Format: Saurav D. Haldar, Amanda Huff, Thatcher R. Heumann, Maureen Berg, Anna Ferguson, Su Jin Lim, Hao Wang, Amy M. Thomas, Julie M. Nauroth, Marina Baretti, Katherine M. Bever, Mark Yarchoan, Daniel A. Laheru, Elizabeth M. Jaffee, Nilofer S. Azad, Neeha Zaidi. Safety and immunogenicity of a first-in-human mutant KRAS long peptide vaccine combined with ipilimumab/nivolumab in resected pancreatic cancer: Preliminary analysis from a phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT036.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults. A fusion between DNAJB1, a heat shock chaperone protein, and PRKACA, the catalytic domain of protein kinase A (PKA) has been identified as a signature genomic event in FLC, but the effect of this fusion on the tumor immune microenvironment is not understood. We created an orthotopic, syngeneic model of FLC (TIBx-FLC) by inducing the DNAJB1-PRKACA fusion in a murine hepatoblastoma-derived cell line (TIBx). CD8 T cells isolated from TIBx-FLC tumors demonstrated markedly impaired activation as compared to CD8 T cells isolated from control TIBx tumors. We investigated metabolic programming as a potential mechanism for DNAJB1-PRKACA immunosuppression in FLC. Labeled glucose metabolomics performed on TIBx-FLC and TIBx tumor cells demonstrated a metabolic shift away from aerobic metabolism to an increased glucose contribution towards the hexosamine biosynthetic pathway and purine synthesis, which requires glutamine as a nitrogen source. As compared to the parental TIBx cell line, the TIBx-FLC cell line demonstrated high sensitivity to glutamine antagonism in vitro, consistent with glutamine addiction. Systemic treatment of BALB/c mice bearing TIBx-FLC tumors with JHU-083, a glutamine antagonist, in combination with immune checkpoint inhibitor therapy enhanced survival as compared to vehicle or monotherapy. These data identify altered glutamine metabolism as a target in FLC, and may provide an explanation for immune suppression seen in the FLC tumor microenvironment. Citation Format: Zeal Kamdar, Tamara Lopez-Vidal, Kathryn Howe, Kabeer Munjal, Ali Saeed, Daniel Zabransky, Daniel Shu, Gabriella Longway, Emma Kartalia, James Leatherman, Aditya Mohan, Pratik Khare, Cissy Zhang, Anne Le, Erika Pearce, Mark Furth, Marina Baretti, Robert Leone, Elizabeth Jaffee, Mark Yarchoan. DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma induces glutamine addiction and an immunosuppressive tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3679.