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.

项目总结/摘要 最近，在采用过继性细胞转移（ACT）的癌症治疗中已经取得了显著的进展。 肿瘤特异性“杀伤”，CD 8 + T细胞。各种工程化T细胞，包括嵌合抗原受体T（CAR-T） 细胞作为新形式的癌症疗法显示出巨大的潜力。然而，一个不利的肿瘤微环境 (TME)阻碍T细胞浸润和存活并诱导T细胞功能障碍（即，'exhaustion'），使 治疗短暂的有益效果。当T细胞被抗原刺激时，耗尽的T细胞（TEX）产生 长时间，这驱动了一个明确的分化过程，涉及主要的转录和 T细胞的表观遗传变化。因此，已经尝试促进肿瘤内T细胞增殖。 但挑战是过继转移的T细胞的长期存活和功效差 在实体瘤中仍然存在。因此，这项提案的目标是设计T细胞，使其更好地渗透和 在肿瘤内存活，以提供强大、持久的抗肿瘤T细胞免疫。 通过结合（1）Kaech博士实验室在效应和记忆T细胞发育方面的专业知识，（2） 王博士实验室在表观基因组/基因组数据的综合分析，和（3）钟博士在蛋白质 工程，这项研究将提供新的解决方案，目前的限制在ACT。初步研究 生成了CD 8 +T细胞的表观遗传和转录图谱，并分析了CD 8 +T细胞的转录因子网络。 最具肿瘤杀伤性、肿瘤浸润性的“效应”T细胞状态，持久的“驻留记忆”T细胞状态， 功能失调的“耗尽”T细胞状态。基于对T细胞分化状态的理解， 旨在设计关键的转录因子程序，驱动所需的T细胞状态，并设计新的方法 重定向T细胞耗竭状态以切换所需的效应器和记忆状态，并暂时和 组合地原位控制过继转移的T细胞的细胞状态特异性TF。 这种新型T细胞工程平台被称为SMARTER（特异性修饰物辅助 具有可调节性的T细胞重编程）。为了产生更聪明的T细胞，在Aim 1中， 将被设计成系统地鉴定新的细胞状态特异性转录因子。在目标2中，合成机械 将被开发用于将衰竭信号重新连接到特定的分化程序。最后，在目标3中，临床上 将开发可用的合成生物学方法，以实现对细胞的时间和组合控制， 特定状态的修饰符。这个SMARTER平台将有效地将T细胞转化为“聪明而顽强的 士兵”。这些增强的T细胞不仅能有效地渗透和杀死癌细胞，还能保留癌细胞。 它们的“敌人”的免疫记忆，并长期驻留在肿瘤部位，导致完全缓解。