Abstract A004: Neoantigen Vaccine for Neoadjuvant Therapy of Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive malignant tumor with a very poor prognosis and highest mortality amongst the commonly diagnosed cancers. The 5-year survival rate has insufficiently improved from 2% in 1975 to 12.8% in 2024 and new cases are rising annually. The current standard of care for patients with PDAC is multiagent chemotherapeutic regimens, all have a survival benefit of 2 to 6 months compared with single-agent gemcitabine. While immune checkpoint blockade (ICB) immunotherapy has been effective for other types of cancers, it has limited efficacy for PDAC. With a clear need for improved standard of care, recent clinical trials with immune modulating therapies have shown promise for treating PDAC. Neoantigen vaccines are a potent means of generating tumor-specific T cell responses and have recently demonstrated clinical success in the treatment of various cancers. We explored the potential of neoantigen MHC Class I epitope vaccines in a translationally relevant pre-clinical murine model of PDAC. To identify the candidate neoantigens, we did whole genome sequencing and paired whole transcriptome sequencing using a KPC cell line derived from an autochthonous H2b-expressing tumor. The sequencing files were analyzed using a proprietary neoantigen prediction algorithm (MyNeo Therapeutics, Ghent, Belgium) to generate a prioritized neoantigen list. Sequencing data was initially analyzed to identify gene variants, including somatic mutations, insertions/deletions (Indels), gene fusions, transposable elements, neo-isoforms, and long coding RNA small protein-coding open reading frames. This algorithm ranks immunogenic neoantigens for eliciting both CD4+ and CD8+ T cells. The identified gene variants were translated into the respective peptide sequences in silico. To validate the neoantigen immunogenicity, we immunized mice with high-ranking peptides based on the MyNeo algorithm and IFNg production by splenocytes was measured by ELISpot assay. Mice were vaccinated with peptide pool or adjuvant poly I:C as control before implanting the KPC cell line orthotopically in the pancreas. Mice were also treated with anti-PD-1 and tumor growth was monitored by ultrasound imaging for up to 4 weeks. We found significant decrease in the primary tumor size after vaccination with peptide pool as compared to poly I:C alone. We are converting peptide to nucleotide sequence to construct neoantigen MVA (neoMVA) vaccine and evaluate the immunogenicity of this approach by assessing anti-tumor efficacy, enhancement of response to ICB, and activation of anti-tumor immunity in the PDAC cancer model. To further translate our success towards the clinic we will evaluate the feasibility of generating neoMVA vaccines from tumor biopsies of consented patients and examine their capacity to elicit anti-tumor T cell responses in HLA-transgenic mice (HLA: A*101, A*0201, B*0702). Our goal is to translate these findings towards a clinical evaluation of a neoMVA vaccine in the neoadjuvant setting, with the hope of improving patient long-term outcomes. Citation Format: Deepika Bhullar, Angel Gutierrez-Franco, Marcal Yll Pico, Ferdynand Kos, Teodora Kaltcheva, Shannon Dempsey, Colt Egelston, Don Diamond. Neoantigen Vaccine for Neoadjuvant Therapy of Pancreatic Cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A004.