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

项目摘要 目前还没有一种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 基于它们的疫苗往往失败，因为免疫个体具有适当的T细胞太少， 受体或完全缺乏它们。我们研究计划的总体目标是通过以下方式解决这一问题： 开发可注射的纳米试剂，其将工程化的T细胞导入外周T细胞库 受体（TCR），最佳结合最普遍的疫苗表位。具体来说，我们假设 定制的特异性可以通过将抗癌疫苗与 这些技术在遗传上使内源性CD 8 T细胞能够表达对疫苗特异性的TCR。我们 进一步假设，我们可以使用这个平台来编程具有定义的MHC II类的CD 4 T辅助细胞， 限制性TCR，从而改善肿瘤特异性CD 8淋巴细胞和B细胞对肿瘤抗原的应答 与传统的免疫方法相比。我们的多学科免疫学家，生物工程师 遗传学家已经证实，肌肉注射纳米粒子可以传递工程TCR 基因进入宿主T细胞，使它们识别癌症疫苗抗原。在疫苗诱导的快速扩增之后， 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， 通过将外源性抗原特异性TCR引入患者的T细胞库来增强免疫力。作为基本步骤， 为了实现这一目标，我们提出了以下具体目标：（1）测试更广泛的适用性和长期- 将疫苗特异性编程到CD 8 + T细胞中的安全性术语，（2）量化宿主的程度 用TCR编程的CD 4 + T细胞针对癌症疫苗抗原增强免疫应答，以及（3） 确定提供优化的CD 4 T细胞帮助和逆转肿瘤免疫逃避机制是否能够在 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 我们的研究所产生的系统将提供一个概念框架，用于设计一个广泛的剧目， 基因修饰系统旨在产生针对任何类型癌症的选择性免疫力。使用这些在 该诊所不仅可以使癌症疫苗更有效，而且还可以减少疫苗失败的可能性。

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.