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Rational in situ programming of cancer vaccine-responding T-cell clones

癌症疫苗反应 T 细胞克隆的合理原位编程

基本信息

批准号：
10268045
负责人：
Matthias Stephan
金额：
$ 12.66万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10268045
关键词：
3-Dimensional Adjuvant Affinity Age Antibodies Antigens Antitumor Response B-Lymphocytes Binding Biomedical Engineering CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cancer Vaccine Related Development Cancer Vaccines Chimeric Proteins Clinic Clinical Research Clone Cells Custom Data Databases Disease Engineering Ensure Epitopes Failure Frequencies Gene-Modified Genes Goals Homeostasis Human Immune Immune response Immune system Immunity Immunization Immunize Immunologist In Situ Individual Information Systems Injectable Intramuscular KPC model Knowledge Ligands Lymph Lymphocyte MHC Class II Genes Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Measures Memory B-Lymphocyte Methods Mus Pancreatic Ductal Adenocarcinoma Patients Peripheral Persons Pharmaceutical Preparations Phenotype Physicians Plasmids Polymers Population Provenge Reagent Research Research Proposals Safety Self Tolerance Specificity Survival Rate System T cell receptor repertoire sequencing T cell response T memory cell T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte T-cell receptor repertoire Techniques Technology Testing Therapeutic Transgenes Translations Tumor Antigens Tumor Escape Tumor Immunity Vaccine Antigen Vaccines Wilms Tumor Suppressor 1 activated protein C receptor anti-cancer antigen-specific T cells arm base bioinformatics tool cancer cell cancer immunotherapy cancer regression cancer type clinical efficacy clinically relevant design engineered T cells experience fighting immunological status immunoregulation improved men mesothelin multidisciplinary nanoparticle nanoparticle delivery nanoparticle drug neoantigens pancreatic cancer model programs receptor response side effect tumor virtual

项目摘要

Project Summary Currently no method exists that would allow physicians to rapidly and reliably establish T-cell immunity against tumor antigens. Bioinformatics tools can predict antigens on cancer cells that are recognized by T cells, but the vaccines based on them often fail because the immunized individuals have too few T cells with the appropriate receptors or lack them altogether. The overall goal of our research proposal is to resolve this problem by developing injectable nanoreagents that introduce into the peripheral T-cell repertoire engineered T-cell receptors (TCRs) that optimally bind the most prevalent vaccine epitope. Specifically, we hypothesize that a customized specificity can be programmed into T cell populations by combining anti-cancer vaccines with techniques that genetically enable endogenous CD8 T cells to express TCRs specific for the vaccines. We further hypothesize that we can use this platform to program CD4 T helper cells with defined MHC class-II- restricted TCRs, and thereby improve tumor-specific CD8 lymphocyte and B cell responses to tumor antigens compared to conventional immunization methods. Our multidisciplinary team of immunologists, bioengineers and geneticists has already established that intramuscularly injected nanoparticles can deliver engineered TCR genes into host T cells so they recognize cancer vaccine antigen. Following rapid vaccine-induced expansion, nanoparticle-programmed T cells ultimately differentiate into long-lived memory T cells. Our long-term goal is to develop a full suite of nanoparticles drugs that would allow physicians to rapidly establish anti-cancer immunity by introducing exogenous antigen-specific TCRs into the patient's T-cell pool. As essential steps toward achieving this goal, we propose the following Specific Aims: (1) To test the wider applicability and long- term safety of programming vaccine specificity into CD8+ T cells, (2) to quantify the degree to which host CD4+ T cells programmed with TCRs to cancer-vaccine antigens boost the immune response, and (3) to determine if providing optimized CD4 T-cell help and reversing tumor immune evasion mechanisms enables in situ programmed vaccine-specific T cells to eradicate disease. We believe that data, reagents, and technology systems generated by our research will provide a conceptual framework for the design of a broad repertoire of gene modification systems designed to generate selective immunity against any type of cancer. Using these in the clinic could make cancer vaccines not only more effective, but also reduce the likelihood of vaccine failure.

项目总结