Cancer Immune-Interception in a Spontaneous Non-Human Primate Model of Lynch Syndrome

自发性非人类灵长类动物林奇综合征模型中的癌症免疫拦截

• 批准号: 10536878
• 负责人: STANTON BRADLEY GRAY
• 金额: $ 64.63万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536878
• 关键词: Adaptive Immune System; Adjuvant; Adrenal Glands; Affect; Agonist; American; Animal Model; Antigen-Presenting Cells; Antigens; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Vaccines; Catalogs; Cell Line; Cells; Chemopreventive Agent; Clinical Chemoprevention; Clinical Trials; Coculture Techniques; Code; Colorectal; Colorectal Cancer; Combined Vaccines; Coupled; Cytotoxic T-Lymphocytes; DNA; Development; Endometrium; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Familial colorectal cancer; Fostering; Genes; Genomics; Germ-Line Mutation; Goals; Hereditary Nonpolyposis Colorectal Neoplasms; Human; Immune; Immune system; Immunologic Monitoring; Immunologics; In Vitro; Incidence; Industry Collaboration; Intercept; Knowledge; Life; MHC Class I Genes; MLH1 gene; Macaca mulatta; Malignant Neoplasms; Mass Spectrum Analysis; Microsatellite Repeats; Mismatch Repair; Mission; Modeling; Mucous Membrane; Naproxen; Non-Steroidal Anti-Inflammatory Agents; Normal Cell; Outcome; Ovary; Patients; Pattern; Penetration; Peptides; Peripheral Blood Mononuclear Cell; Permeability; Phase; Physiological; Play; Population; Population Genetics; Prevention; Preventive vaccine; Public Health; Publishing; Recurrence; Reporting; Research; Rhesus; Safety; Small Intestines; Stomach; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Toll-like receptors; Translations; United States National Institutes of Health; Vaccination; Vaccines; Validation; base; bioinformatics pipeline; cancer cell; cancer prevention; cancer type; cell killing; co-clinical trial; cohort; cytokine; cytotoxic; cytotoxic CD8 T cells; cytotoxicity; first-in-human; gene repair; high risk; immune activation; immune stimulant; immunogenic; immunogenicity; innovation; insertion/deletion mutation; neoantigens; next generation sequencing; nonhuman primate; novel; response; tool; translation to humans; tumor; vaccine development; vaccine platform

ABSTRACT Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC) affecting >1 million Americans. LS is caused by germline mutations in one of four DNA mismatch repair (MMR) genes. Normal colorectal epithelial cells in LS patients become MMR deficient after a somatic ‘second’ hit generating the accu- mulation of hundreds of insertion-deletion mutations (indels) in microsatellite sequences. These indels generate frameshift peptides (FSP) that become neoantigens (neoAg) and stimulate the adaptive immune system. We have previously reported that adaptive immune genes are highly expressed in LS pre-cancers, and we have generated a detailed neoAg catalog with >1,000 FSP neoAg from a cohort of LS pre-cancers and early-stage CRCs using next-generation sequencing tools coupled with a state-of-the-art bioinformatics pipeline. In addition, we have published the results of a phase Ib chemoprevention clinical trial in LS patients using naproxen showing immune-activation of colorectal mucosa resident cells. Taken together, these results point strongly towards the development of a vaccine for ‘recurrent’ and ‘shared’ LS-associated tumor neoAg combined with naproxen for pan-cancer prevention in the LS population. However, the main knowledge gap remains to select the most opti- mal neoAg peptides and to establish the efficacy and safety of the vaccination in a reliable animal model that allows immediate human translation. Rhesus macaques are a promising non-human primate (NHP) model dis- playing the closest genomic resemblance to humans. Our research team has reported the first colony of spon- taneous LS in rhesus carrying a germline mutation in MLH1. In addition, we are partnering with industry collab- orators in AMAL Therapeutics that have developed an innovative vaccination platform called KISIMA, integrating several selected FSP in tandem with a cell-permeable peptide fostering cell penetration, and a toll-like receptor agonist that acts as a self-adjuvant. Our central hypothesis is that our state-of-the-art bioinformatics pipeline for neoAg prediction will lead to the identification of the most immunogenic, recurrent across tumors, and shared among LS-associated tumor types FSP neoAg to be integrated in the KISIMA self-adjuvant vaccine platform, which will render a strong immunogenicity in combination with naproxen. To explore this hypothesis, we propose three specific aims: 1. To validate in vitro the immunogenicity of the top 150 recurrent neoAg shared by LS non-colorectal tumors using ELISpot, ELISA, and cytokine assays using PBMCs and CD8+ T cells from healthy human donors; 2. To develop artificial antigen-presenting cells (aAPC) expressing human LS neoAg to validate the cytotoxicity of neoAg-enriched T cells; and 3. To assess the immunogenicity of a neoAg combination using the novel self-adjuvant vaccine platform KISIMA alone and in combination with naproxen in a co-clinical trial in LS rhesus. The proposal is highly innovative because is developing a novel self-adjuavnt vaccine platform in a unique spontaneous NHP model of LS. The proposed research will significantly impact the field because it is a stepping stone to develop a Phase I first-in-human clinical trial to test a novel CRC vaccine for LS patients.

摘要