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：
10663869
负责人：
Matthias Stephan
金额：
$ 44.63万
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/10663869
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 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 Injectable Intramuscular KPC model Knowledge Ligands Lymph Lymphocyte MHC Class II Genes Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Maps Measures Memory B-Lymphocyte Methods Mus Pancreatic Ductal Adenocarcinoma Patients Peripheral Persons Pharmaceutical Preparations Phenotype Physicians Plasmids 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 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 nanopolymer neoantigens pancreatic cancer model programs receptor response side effect technology platform 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.

项目摘要目前尚无将医生迅速可靠地建立T细胞免疫的方法肿瘤抗原。生物信息学工具可以预测T细胞识别的癌细胞上的抗原，但是基于它们的疫苗通常会失败，因为免疫个体的T细胞太少受体或完全缺乏它们。我们研究建议的总体目标是通过开发可注射的纳米激素，这些纳米调子引入外围T细胞曲目工程T细胞最佳结合最普遍的疫苗表位的受体（TCR）。具体来说，我们假设可以通过将抗癌疫苗与从遗传上讲，可以使内源性CD8 T细胞表达对疫苗特有的TCR。我们进一步假设我们可以使用此平台对CD4 T辅助细胞进行编程，并具有定义的MHC类-II- 受限的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常规免疫方法相比。我们的免疫学家，生物工程师的多学科团队遗传学家已经确定肌肉内注射的纳米颗粒可以提供工程的TCR 基因进入宿主T细胞，从而识别癌症疫苗抗原。在快速疫苗诱导的膨胀之后，纳米颗粒编程的T细胞最终分化为长寿命的记忆T细胞。我们的长期目标是开发一套完整的纳米颗粒药物，这些药物将使医生能够快速建立抗癌药通过将外源性抗原特异性TCR引入患者的T细胞库中，免疫。作为基本步骤为了实现这一目标，我们提出以下特定目的：（1）测试更广泛的适用性和长期编程疫苗特异性对CD8+ T细胞的术语安全性，（2）以量化宿主的程度用TCRS编程的CD4+ T细胞以癌 - 疫苗抗原提高免疫反应，（3）确定是否提供优化的CD4 T细胞帮助并逆转肿瘤免疫逃避机制原位编程的疫苗特异性T细胞消除了疾病。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曲目提供一个概念框架旨在针对任何类型的癌症产生选择性免疫的基因修饰系统。使用这些该诊所可以使癌症疫苗不仅更有效，还可以减少疫苗衰竭的可能性。