Johannes Gebert1, Ozkan Gelincik2, Mine Oezcan-Wahlbrink3, Jason D Marshall4, Alejandro Hernandez-Sanchez3, Katharina Urban3, Mark Long5, Eduardo Cortes5, Elena Tosti6, Eva-Maria Katzenmaier3, Yurong Song4, Ali Elsaadi2, Nan Deng7, Eduardo Vilar7, Vera Fuchs3, Nina Nelius3, Yan P Yuan8, Aysel Ahadova3, Shizuko Sei9, Robert H Shoemaker9, Asad Umar9, Lei Wei5, Song Liu5, Peer Bork10, Winfried Edelmann6, Magnus von Knebel Doeberitz11, Steven M Lipkin12, Matthias Kloor13. 1. Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany. Electronic address: johannes.gebert@med.uni-heidelberg.de. 2. Weill Cornell Medical College, New York, New York. 3. Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany. 4. Cancer ImmunoPrevention Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland. 5. Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York. 6. Department of Cell Biology, Albert Einstein College of Medicine, New York, New York. 7. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. 8. European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany. 9. Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland. 10. European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany; Max Delbrück Centre for Molecular Medicine, Berlin, Germany; Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany. 11. Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany. Electronic address: magnus.knebel-doeberitz@med.uni-heidelberg.de. 12. Weill Cornell Medical College, New York, New York. Electronic address: stl2012@med.cornell.edu. 13. Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center, Heidelberg, Germany. Electronic address: matthias.kloor@med.uni-heidelberg.de.
Abstract
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. Published by Elsevier Inc.
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. Published by Elsevier Inc.
Authors: Alejandro Hernandez-Sanchez; Mark Grossman; Kevin Yeung; Shizuko S Sei; Steven Lipkin; Matthias Kloor Journal: J Immunother Cancer Date: 2022-06 Impact factor: 12.469