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：
10412138
负责人：
Matthias Stephan
金额：
$ 46.42万
依托单位：
FRED HUTCHINSON CANCER 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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412138
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 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 vaccine failure 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.

项目概要目前尚无方法可以让医生快速、可靠地建立 T 细胞免疫肿瘤抗原。生物信息学工具可以预测 T 细胞识别的癌细胞上的抗原，但基于它们的疫苗常常会失败，因为免疫个体的 T 细胞太少，且具有适当的免疫功能。受体或完全缺乏受体。我们研究计划的总体目标是通过以下方式解决这个问题开发可注射纳米试剂，将其引入外周 T 细胞库工程化 T 细胞与最常见的疫苗表位最佳结合的受体（TCR）。具体来说，我们假设通过将抗癌疫苗与基因技术使内源性 CD8 T 细胞能够表达疫苗特异的 TCR。我们进一步假设我们可以使用这个平台来编程具有明确的 MHC II 类的 CD4 T 辅助细胞限制性 TCR，从而改善肿瘤特异性 CD8 淋巴细胞和 B 细胞对肿瘤抗原的反应与传统的免疫方法相比。我们的多学科团队由免疫学家、生物工程师组成遗传学家已经确定，肌肉注射纳米颗粒可以提供工程 TCR 将基因导入宿主 T 细胞，以便它们识别癌症疫苗抗原。在疫苗引起的快速扩张之后，纳米颗粒编程的 T 细胞最终分化为长寿命记忆 T 细胞。我们的长期目标是开发一整套纳米颗粒药物，使医生能够快速建立抗癌药物通过将外源抗原特异性 TCR 引入患者的 T 细胞库来获得免疫力。作为必要步骤为实现这一目标，我们提出以下具体目标：（1）测试更广泛的适用性和长期性将疫苗特异性编程到 CD8+ T 细胞中的术语安全性，(2) 量化宿主的程度用 TCR 编程的 CD4+ T 细胞可产生癌症疫苗抗原，从而增强免疫反应，并且 (3) 确定提供优化的 CD4 T 细胞帮助和逆转肿瘤免疫逃避机制是否能够实现原位编程疫苗特异性 T 细胞来根除疾病。我们相信数据、试剂和技术我们的研究产生的系统将为设计广泛的系统提供一个概念框架旨在产生针对任何类型癌症的选择性免疫力的基因修饰系统。使用这些该诊所不仅可以使癌症疫苗更加有效，还可以降低疫苗失败的可能性。