Abstract IA018: Cancer immune-interception in Lynch Syndrome: Neoantigen-based vaccine development


 Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer and also conveys significantly increased risks for several other malignancies, including endometrial, small bowel, gastric, ovarian, adrenocortical tumors, and others. LS results from a heterozygous germline mutation in one of four DNA mismatch repair (MMR) genes. The acquisition of a somatic “second hit” causes affected cells to lose the ability to repair DNA mismatch replication errors that frequently occur in microsatellite regions of the genome. Consequently, hundreds to thousands of small insertion/deletions (indels) accumulate in these regions, and when expressed, result in frameshift peptides that are recognized as neoantigens that are then presented on the cell surface via the major histocompatibility complexes (MHC-I/II) for immune cell recognition. Vaccine development efforts in this high-risk population have been challenged by the substantial inter-individual variability in both the set of expressed neoantigens and MHC I/II responses. Yet, recent advances in next-generation sequencing and associated bioinformatic approaches are now allowing for more accurate profiling of the most frequently recurring and shared mutated neoantigens in LS-associated tumors. This allows for identification of the most immunogenic neoantigens that can be incorporated into different vaccine platforms to test the development of a population-based vaccine. The Vilar Lab has collaborated with industry and academic partners such as Nouscom, s.r.l. and the National Cancer Institute to develop two different clinical trials to bring new vaccines to the LS population based on mutated neoantigens and tumor associated antigens. In this presentation, we will focus on mutated neoantigen-based strategies and present the Phase I clinical trial (NCT05078866) using a viral-based vaccine including 209 distinct neoantigens. The primary endpoint of this trial is safety and immunogenicity. A total of 45 participants will be enrolled to receive a prime and boost vaccination. Different secondary biomarkers will explore immunological aspects of this novel immune-interception strategy.
 Citation Format: Eduardo Vilar-Sanchez. Cancer immune-interception in Lynch Syndrome: Neoantigen-based vaccine development [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA018.