Thursday, April 25, 2024
4/25/2024
ABSTRACT Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC) affecting >1 million Americans. LS is caused by germline mutations in one of four DNA mismatch repair (MMR) genes. Normal colorectal epithelial cells in LS patients become MMR deficient after a somatic ‘second’ hit generating the accu- mulation of hundreds of insertion-deletion mutations (indels) in microsatellite sequences. These indels generate frameshift peptides (FSP) that become neoantigens (neoAg) and stimulate the adaptive immune system. We have previously reported that adaptive immune genes are highly expressed in LS pre-cancers, and we have generated a detailed neoAg catalog with >1,000 FSP neoAg from a cohort of LS pre-cancers and early-stage CRCs using next-generation sequencing tools coupled with a state-of-the-art bioinformatics pipeline. In addition, we have published the results of a phase Ib chemoprevention clinical trial in LS patients using naproxen showing immune-activation of colorectal mucosa resident cells. Taken together, these results point strongly towards the development of a vaccine for ‘recurrent’ and ‘shared’ LS-associated tumor neoAg combined with naproxen for pan-cancer prevention in the LS population. However, the main knowledge gap remains to select the most opti- mal neoAg peptides and to establish the efficacy and safety of the vaccination in a reliable animal model that allows immediate human translation. Rhesus macaques are a promising non-human primate (NHP) model dis- playing the closest genomic resemblance to humans. Our research team has reported the first colony of spon- taneous LS in rhesus carrying a germline mutation in MLH1. In addition, we are partnering with industry collab- orators in AMAL Therapeutics that have developed an innovative vaccination platform called KISIMA, integrating several selected FSP in tandem with a cell-permeable peptide fostering cell penetration, and a toll-like receptor agonist that acts as a self-adjuvant. Our central hypothesis is that our state-of-the-art bioinformatics pipeline for neoAg prediction will lead to the identification of the most immunogenic, recurrent across tumors, and shared among LS-associated tumor types FSP neoAg to be integrated in the KISIMA self-adjuvant vaccine platform, which will render a strong immunogenicity in combination with naproxen. To explore this hypothesis, we propose three specific aims: 1. To validate in vitro the immunogenicity of the top 150 recurrent neoAg shared by LS non-colorectal tumors using ELISpot, ELISA, and cytokine assays using PBMCs and CD8+ T cells from healthy human donors; 2. To develop artificial antigen-presenting cells (aAPC) expressing human LS neoAg to validate the cytotoxicity of neoAg-enriched T cells; and 3. To assess the immunogenicity of a neoAg combination using the novel self-adjuvant vaccine platform KISIMA alone and in combination with naproxen in a co-clinical trial in LS rhesus. The proposal is highly innovative because is developing a novel self-adjuavnt vaccine platform in a unique spontaneous NHP model of LS. The proposed research will significantly impact the field because it is a stepping stone to develop a Phase I first-in-human clinical trial to test a novel CRC vaccine for LS patients.
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