On the development of a neoantigen vaccine for the prevention of Lynch Syndrome

Abstract

Lynch Syndrome (LS) is an autosomal dominant genetic condition that causes a high risk of colorectal cancer. The hallmark of LS is genetic instability as a result of mismatch repair (MMR) deficiency, particularly in repetitive low complexity regions called microsatellites (MS). MLH1−/− mice deficient in MMR are prone to developing tumors in the colon, upon oral administration of dextran sodium sulfate (DSS), at a rate of more than 70%. Using this LS mouse model, we found a novel tumor neo‐antigen from a deletion mutation of the coding MS in the SENP6 gene that prevented tumorigenesis or hindered tumor growth rate in immunized mice. This was accomplished via high throughput exome sequencing of DSS‐induced colorectal tumors in the MLH1−/− mice and predicting the most highly immunogenic mutant gene products processed and presented as antigens in C57BL/6 MHC‐I molecules. Throughout our study, we were able to prove the validity of the vaccine by analyzing the colorectal tumors in immunized DSS‐treated mice using either our epitope, called Sp6D1, or an unrelated peptide as a negative control. Tumors developed in this context were found to be antigenic and Sp6D1‐specific CD8+ tumor infiltrating lymphocytes were detected by flow cytometry and cytotoxic T lymphocytes (CTL) killing assays. Additionally, immunohistochemistry showed that tumor‐adjacent tertiary lymphoid organs were a potentially significant source of CD8+ lymphocytes. Altogether, our results indicate that there may be a protective effect to patients carrying LS mutations through the induction of a peptide‐specific CTL response from the use of neoepitope vaccination.

Hereditary Colorectal Cancer Syndromes: Molecular Genetics and Precision Medicine

“…In addition, several clinical and pre-clinical trials for LS and dMMR cancer are underway to test the safety and immunogenicity of frameshift peptide (FSP) neoantigen-based vaccine [ 94 , 95 , 96 ]. In a phase I/Iia clinical trial, 22 patients with advanced dMMR CRC received FSP neoantigen-based vaccine, and the results showed that vaccine-induced humoral and cellular immune responses were observed in all patients and no vaccination-induced severe adverse events occurred [ 95 ].…”