TY - JOUR
T1 - Recurrent Frameshift Neoantigen Vaccine Elicits Protective Immunity With Reduced Tumor Burden and Improved Overall Survival in a Lynch Syndrome Mouse Model
AU - Gebert, Johannes
AU - Gelincik, Ozkan
AU - Oezcan-Wahlbrink, Mine
AU - Marshall, Jason D.
AU - Hernandez-Sanchez, Alejandro
AU - Urban, Katharina
AU - Long, Mark
AU - Cortes, Eduardo
AU - Tosti, Elena
AU - Katzenmaier, Eva Maria
AU - Song, Yurong
AU - Elsaadi, Ali
AU - Deng, Nan
AU - Vilar, Eduardo
AU - Fuchs, Vera
AU - Nelius, Nina
AU - Yuan, Yan P.
AU - Ahadova, Aysel
AU - Sei, Shizuko
AU - Shoemaker, Robert H.
AU - Umar, Asad
AU - Wei, Lei
AU - Liu, Song
AU - Bork, Peer
AU - Edelmann, Winfried
AU - von Knebel Doeberitz, Magnus
AU - Lipkin, Steven M.
AU - Kloor, Matthias
N1 - Publisher Copyright:
© 2021
PY - 2021/10
Y1 - 2021/10
N2 - Background & Aims: DNA mismatch repair deficiency 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. Individuals with LS 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 yet been demonstrated. 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 4 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 4 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. Conclusions: Our preclinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.
AB - Background & Aims: DNA mismatch repair deficiency 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. Individuals with LS 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 yet been demonstrated. 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 4 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 4 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. Conclusions: Our preclinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.
KW - Colorectal Cancer
KW - Frameshift Neoantigens
KW - Lynch Syndrome
KW - Mouse Model
KW - Preventive Cancer Vaccine
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UR - http://www.scopus.com/inward/citedby.url?scp=85112532004&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2021.06.073
DO - 10.1053/j.gastro.2021.06.073
M3 - Article
C2 - 34224739
AN - SCOPUS:85112532004
SN - 0016-5085
VL - 161
SP - 1288-1302.e13
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -