Next-generation T cell therapy: SMARTER T cells for enhanced and durable anti-tumor immunity

下一代 T 细胞疗法：SMARTER T 细胞可增强且持久的抗肿瘤免疫力

• 批准号: 10644940
• 负责人: Hokyung Kay Chung
• 金额: $ 15.98万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644940
• 关键词: Adopted; Adoptive Cell Transfers; Antigens; Antitumor Response; Atlases; Automobile Driving; Binding; Bioinformatics; CD8-Positive T-Lymphocytes; Cell Reprogramming; Cell membrane; Cells; Clinical; Code; Combinatorics; Disease remission; Doctor of Philosophy; Effectiveness; Engineering; Epigenetic Process; Eragrostis; Evaluation; Fostering; Functional disorder; Genetic; Genetic Engineering; Genetic Transcription; Goals; Human; Immunity; Immunologic Memory; Immunology; Immunotherapy; In Situ; Individual; Infiltration; Intelligence; Knowledge; Malignant Neoplasms; Memory; Methodology; Methods; Modification; Pathway interactions; Pharmaceutical Preparations; Process; Proliferating; Protein Engineering; Receptor Signaling; Rejuvenation; Research; Resistance; Route; Signal Pathway; Signal Transduction; Site; Soldier; Solid Neoplasm; Specificity; T cell differentiation; T cell infiltration; T cell therapy; T memory cell; T-Cell Development; T-Cell Transformation; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Transcriptional Regulation; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; cancer cell; cancer therapy; chimeric antigen receptor T cells; clinically relevant; combinatorial; cytotoxic; design; effector T cell; engineered T cells; epigenomics; exhaust; exhaustion; genomic data; immune checkpoint blockade; improved; in vivo; in vivo Model; innovation; next generation; novel; novel strategies; prevent; programmed cell death protein 1; programs; receptor; single cell sequencing; small hairpin RNA; synthetic biology; tissue resident memory T cell; trafficking; transcription factor; transcriptional reprogramming; translational applications; translational potential; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Recently, remarkable progress has been made in cancer treatment employing adoptive cell transfer (ACT) of tumor-specific “killer”, CD8+ T cells. Various engineered T cells including chimeric antigen receptor T (CAR-T) cells, have shown great potential as new forms of cancer therapies. However, a hostile tumor microenvironment (TME) impedes T cell infiltration and survival and induces T cell dysfunction (i.e., ‘exhaustion’), making the beneficial effects of the therapy transient. Exhausted T cells (TEX) arise when T cells are stimulated by antigen for prolonged periods, which drives a defined differentiation process involving major transcriptional and epigenetic changes in T cells. Thus, there have been attempts to promote intratumoral T cell trafficking/proliferation but challenges with poor long-term survival and efficacy of adoptively transferred T cells in solid tumors still remain. Therefore, the goal of this proposal is to engineer T cells that better infiltrate and survive inside tumors to provide robust, durable anti-tumor T cell immunity. By combining (1) the expertise of the Dr. Kaech lab in effector and memory T cell development, (2) that of the Dr. Wang lab in integrative analysis of epigenomic/genomic data, and (3) that of Dr. Chung in protein engineering, this research will provide novel solution to the current limitation in ACT. Preliminary research generated epigenetic and transcriptional atlas of CD8+T cells and analyzed the transcription factor networks of the most tumoricidal, tumor-infiltrating “effector” T cell state, the long-lasting “resident-memory” T cell state and dysfunctional “exhausted” T cell state. Based on the understanding of T cell differentiation states, this proposal aims to design key transcription factor programs that drive desired T cell states and devise new methodologies to redirect T cell exhaustion state to toggle desirable effector and memory states and to temporally and combinatorically control the cell-state specific TFs of the adoptively transferred T cells in situ. This new class of T cell engineering platform is termed SMARTER (Specific Modifiers Assisted Reprogramming of T cell Engineered with Regulability). To generate SMARTER T cells, in Aim 1, a new platform will be devised to systemically identify novel cell-state-specific transcription factors. In Aim 2, synthetic machinery will be developed to rewire exhaustion signals to specific differentiation program. Lastly, in Aim 3, a clinically useable synthetic biology methods will be developed to enable temporal and combinatorial control of the cell- state-specific modifiers. This SMARTER platform will effectively transform T cells into “intelligent and tenacious soldiers”. These enhanced T cells will not only effectively infiltrate and kill cancer cells, but also retain the immunological memory of their “foes” and reside long-term at the tumor site, leading to complete remission.

项目摘要/摘要 最近，采用适应性细胞转移（ACT）的癌症治疗取得了显着进展 肿瘤特异性“杀手”，CD8+ T细胞。各种工程T细胞，包括嵌合抗原受体T（CAR-T） 细胞作为癌症疗法的新形式显示出很大的潜力。但是，敌对的肿瘤微环境 （TME）阻碍T细胞浸润和存活，并诱导T细胞功能障碍（即“疲惫”），使得 治疗短暂的有益作用。当T细胞被抗原刺激时，耗尽的T细胞（Tex）出现 长时间的时期，驱动定义的分化过程涉及主要的转录和 T细胞的表观遗传变化。那是试图促进肿瘤内T细胞的尝试 贩运/增殖，但长期生存不良和适当转移的T细胞的挑战，挑战 在实体瘤中仍然保留。因此，该建议的目的是设计更好浸润和的T细胞 在肿瘤内生存以提供坚固，耐用的抗肿瘤T细胞免疫。 通过结合（1）效应器和记忆T细胞开发的Kaech Lab博士的专业知识，（2） Wang博士实验室的表观基因组/基因组数据的综合分析和（3）蛋白质博士的综合分析 工程学，这项研究将为当前ACT的限制提供新的解决方案。初步研究 产生的CD8+T细胞的表观遗传和转录地图集，并分析了转录因子网络 最结核性，肿瘤浸润的“效应子” T细胞状态，持久的“居民记忆” T细胞状态和 功能失调的“疲惫” T细胞状态。基于对T细胞分化状态的理解，该建议 旨在设计关键的转录因子程序，以驱动所需的T细胞状态并设计新方法 重定向t细胞耗尽状态以切换理想的效应子和内存状态以及暂时和 组合控制适当转移的T细胞的细胞态特异性TF。 这种新的T细胞工程平台称为更智能（特定的修饰符辅助 重新编程的T细胞定期设计）。为了生成更智能的T细胞，在AIM 1中，一个新平台 将设计为系统地识别新型细胞态特异性转录因子。在AIM 2中，合成机械 将开发以将精疲力尽的信号重新为特定的分化计划。最后，在AIM 3中，一个临床上 将开发出可用的合成生物学方法，以实现细胞的临时和联合控制 特定于国家的修饰符。这个更聪明的平台将有效地将T细胞转变为“聪明而顽强的 士兵”。这些增强的T细胞不仅将有效浸润并杀死癌细胞，而且还保留了 其“敌人”的免疫记忆，并长期居住在肿瘤部位，从而完全缓解。