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Principal Investigator: Steven M Lipkin
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $345,292
Funding agency: National Cancer Institute
Project 1: Project Summary/Abstract
Lynch syndrome (LS) affects ~1.2 million Americans and predisposes them to colorectal cancer (CRC) and other
malignancies. LS normal cells acquire somatic second mutations and become DNA mismatch repair deficient
(MMRD). MMRD tumors have exceptionally high numbers of frameshift proteins. MMRD mutation rates are so
elevated that precisely the same recurrent mutations are “shared” among tumors from different patients. For
example, TGFBR2 has a 10bp adenine repeat that, when mutated, causes the identical frameshift protein (FSP)
in ~80% of MMRD CRCs. Previously, we showed that (a) 100% of MMRD CRC patients have CD8+ T cells
reactive against MMRD rFSPs, (b) performed first-in-human trials showing that peptide vaccination robustly
upregulates T-cell immunity against rFSP in advanced MMRD cancer patients, and (c) demonstrated functionally
in LS mouse models that vaccination with only four mouse recurrent neoantigens increases CD8+ killer and
CD4+ helper T-cell immune response, reduces CRC burden and prolongs cancer-free survival. As new
preliminary data, we and CAP-IT CRI Computational Tumor Immunology Core (CTIC) Co-PI Getz, a primary
architect of NCI tumor genome atlases, have (a) sequenced the largest number of LS colorectal adenomas and
adenocarcinomas worldwide and identified many promising MMRD recurrent neoantigen vaccine candidates,
(b) used MMRD CRC cell lines, LS patient colon adenoma derived tumoroids and the NCI CPTAC tumor atlas
to confirm that recurrent neoantigens are bona fide expressed as neo-peptides in tumors and (c) showed that in
mice, lipo-nanoparticle RNA (LNP-RNA) rFSP vaccination is significantly more immunogenic than peptide
vaccination. Here we propose to test the hypothesis that LNP-RNA rFSP vaccination elicits LS mouse
CD8+/CD4+ immune response, reduces tumor burden, increases survival (AIM 1), and delineates the most
immunogenic cytotoxic Lynch syndrome patient recurrent neoantigens (AIM 2). This project will identify the most
immunogenic recurrent neoantigens for NCI PREVENT pre-IND vaccine development and NCI CP-NET LS
immunoprevention clinical trials. Importantly, our studies will provide vital mechanistic insights into future
generations of effective patient LNP RNA immunoprevention vaccines.
Terms: <1H-Purin-6-amine><Adenine><Affect><American><Amino Acids><Assay><Atlases><Autologous><Automobile Driving><Bioassay><Biological Assay><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><COVID-19><CV-19><Cancer Burden><Cancer Patient><Cancers><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Checkpoint inhibitor><Class I Genes><Clinical><Clinical Trials><Colonic Adenoma><Colonic Adenomatous Polyp><Colorectal Adenocarcinoma><Colorectal Adenoma><Colorectal Adenomatous Polyp><Colorectal Cancer><Coronavirus Infectious Disease 2019><Correlative Study><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><DNA><Data><Deoxyribonucleic Acid><Disease><Disorder><Familial Nonpolyposis Colon Cancer><Future Generations><Genetic Alteration><Genetic Change><Genetic defect><Genomics><HNPCC><Hereditary Colo-rectal Endometrial Cancer Syndrome><Hereditary Colorectal Endometrial Cancer Syndrome><Hereditary Defective Mismatch Repair Syndrome><Hereditary Non-Polyposis Colon Cancer><Hereditary Nonpolyposis Colo-rectal Cancer><Hereditary Nonpolyposis Colo-rectal Neoplasms><Hereditary Nonpolyposis Colon Cancer><Hereditary Nonpolyposis Colorectal Cancer><Hereditary Nonpolyposis Colorectal Neoplasms><Heterozygote><Human><Immune checkpoint inhibitor><Immune response><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunoprevention><LS/HNPCC><LYT3><Large Bowel Adenocarcinoma><Large Bowel Adenoma><Large Bowel Adenomatous Polyp><Large Intestine Adenocarcinoma><Large Intestine Adenoma><Lynch Syndrome><MHC Class I><MHC Class I Genes><MMR deficiency><Malignant Neoplasms><Malignant Tumor><Mice><Mice Mammals><Microsatellite Instability><Mismatch Repair><Mismatch Repair Deficiency><Modern Man><Murine><Mus><Mutate><Mutation><National Cancer Burden><Non-Polyadenylated RNA><Normal Cell><Patients><Peptides><Post-Replication Mismatch Repair><Proteins><RNA><RNA Gene Products><RNA immunization><RNA vaccination><Recurrence><Recurrent><Ribonucleic Acid><Science><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TGF-Beta Type II Receptor><TGFBR2><TGFBR2 gene><Technology><Testing><Transgenic Mice><Tumor Burden><Tumor Load><Tumor-Infiltrating Lymphocytes><Vaccination><Vaccines><Vitamin B4><adenoma><aminoacid><cancer cell genome><cancer genome><cancer immunology><colon adenoma><colon adenomatous polyp><colon cancer cell line><colon cancer patients><colorectal cancer cell line><colorectal cancer patients><colorectal cancer risk><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytotoxic><develop a vaccine><develop vaccines><development of a vaccine><driving><first in man><first-in-human><gene repair><genome mutation><hereditary non-polyposis colo-rectal cancer><hereditary non-polyposis colorectal cancer><heterozygosity><host response><immune check point><immune check point inhibitor><immune checkpoint><immune system response><immunecheckpoint><immunogenic><immunogenicity><immunoresponse><in vivo><indel><insertion-deletion><insertion-deletion mutation><insertion/deletion><insertion/deletion mutation><insight><killer T cell><mRNA immunization><mRNA vaccination><malignancy><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neo-antigen><neo-antigen vaccine><neo-epitopes><neoantigen vaccine><neoantigens><neoepitopes><neoplasm immunology><neoplasm/cancer><peptide immunization><peptide vaccination><precancer><precancerous><premalignant><repair><repaired><thymus derived lymphocyte><transforming growth factor-beta type II receptor><transforming growth factor-β type II receptor><tumor><tumor genome><tumor immunology><vaccine candidate><vaccine development>