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| Item Type: | Article |
|---|---|
| Title: | Recurrent frameshift neoantigen vaccine elicits protective immunity with reduced tumor burden and improved overall survival in a Lynch syndrome mouse model |
| Creators Name: | Gebert, J. and Gelincik, O. and Oezcan-Wahlbrink, M. and Marshall, J.D. and Hernandez-Sanchez, A. and Urban, K. and Long, M. and Cortes, E. and Tosti, E. and Katzenmaier, E.M. and Song, Y. and Elsaadi, A. and Deng, N. and Vilar, E. and Fuchs, V. and Nelius, N. and Yuan, Y.P. and Ahadova, A. and Sei, S. and Shoemaker, R.H. and Umar, A. and Wei, L. and Liu, S. and Bork, P. and Edelmann, W. and von Knebel Doeberitz, M. and Lipkin, S.M. and Kloor, M. |
| Abstract: | BACKGROUND AND AIMS: DNA mismatch repair deficiency (MMRD) drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. LS individuals are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a Phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not been demonstrated so far. METHODS: A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression and mutation frequency. In silico prediction, in vivo immunogenicity testing and epitope mapping was used to identify candidates for FSP vaccination. RESULTS: We identified four shared FSP neoantigens [Nacad(FSP-1), Maz(FSP-1), Senp6(FSP-1), Xirp1(FSP-1)] that induced CD4/CD8 T cell responses in naïve C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only four FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth and prolonged survival even more effectively than FSP vaccination alone. CONCLUSION: Our pre-clinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention. |
| Keywords: | Colorectal Cancer, Frameshift Neoantigens, Lynch Syndrome, Mouse Model, Preventive Cancer Vaccine, Animals, Mice |
| Source: | Gastroenterology |
| ISSN: | 0016-5085 |
| Publisher: | Elsevier |
| Volume: | 161 |
| Number: | 4 |
| Page Range: | 288-1302.e13 |
| Date: | October 2021 |
| Additional Information: | Copyright © 2021 by the AGA Institute. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license. |
| Official Publication: | https://doi.org/10.1053/j.gastro.2021.06.073 |
| PubMed: | View item in PubMed |
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