A Comprehensive analysis and the impact of promemory gene incorporation on CAR T cell memory differentiation in the context of solid tumors

实体瘤背景下前记忆基因掺入对 CAR T 细胞记忆分化的影响的综合分析

• 批准号: 10528441
• 负责人: Steven James Reed
• 金额: $ 7.01万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528441
• 关键词: Address; Anatomy; Antigens; Antitumor Response; B-Cell Acute Lymphoblastic Leukemia; B-Cell Lymphomas; B-cell precursor acute lymphoblastic leukemia cell; Blood Circulation; CAR T cell therapy; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Survival; Cell physiology; Cells; Cellular biology; Chemotherapy and/or radiation; Child; Clinical; Clinical Research; Clinical Trials; Consensus; Data; Development; Diagnosis; Ectopic Expression; Educational workshop; Engineering; Environment; Evaluation; Exhibits; FDA approved; Foundations; Fred Hutchinson Cancer Research Center; Generations; Genes; Genetic Transcription; Goals; Health Benefit; Hematologic Neoplasms; Immunocompetent; Immunologics; Immunology; Immunotherapeutic agent; Immunotherapy; Individual; Left; Liquid substance; Location; Lymphoid; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Memory; Mentorship; Methods; Modeling; Modification; Multiple Myeloma; Mus; Outcome; Patients; Phenotype; Pre-Clinical Model; Process; Recurrence; Regimen; Relapse; Research; Research Institute; Research Training; Role; Signal Transduction; Solid Neoplasm; Structure; Study models; T cell differentiation; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapy Clinical Trials; Time; Training; Tumor Antigens; Tumor Cell Line; Tumor Escape; Turtles; Universities; Washington; anticancer research; base; cancer care; cancer immunotherapy; cancer therapy; chimeric antigen receptor T cells; clinically relevant; combat; design; effective therapy; effector T cell; exhaust; exhaustion; experimental study; fight against; immunogenicity; lens; member; mouse model; next generation; post-doctoral training; response; side effect; skills; stemness; success; theories; translational framework; trend; tumor; tumor microenvironment

Project summary/abstract CAR T cell immunotherapy has shown increasing success in the early control of liquid tumors including B-cell Acute Lymphoblastic Leukemia (B-ALL), B cell lymphomas, and multiple myeloma. However, establishing CAR T cell-mediated long-term protection has proven challenging, and tumor relapse occurs in approximately 30-50% of patients who showed initial responses to CAR T cell therapy. In many clinical trials, the tumor antigen(+) recurrence has accounted for the majority of total relapse cases, suggesting that the CAR T cells in these patients failed to instill long-term tumor control and protection from tumor relapse. Consistent with the trends observed in CAR T cell therapy clinical trials, preliminary data in our lab from a solid tumor model, has revealed a striking negative-correlation between tumor relapse and the number of CAR T cells detected at the time of relapse. Thus, we hypothesize that effective CAR T cell memory is critical for long-term protection against tumor antigen(+) relapse. Despite the widespread consensus for this hypothesis, limitations in relevant preclinical models have left the field of CAR T cell research lacking in comprehensive studies that directly address CAR T cell memory. To pursue our long-term goal of developing methods to enhance CAR T cell function and memory generation, we have developed a solid tumor model involving murine third-generation CAR T cells, fully immunocompetent mice, and distinct synergistic tumor cell lines. Using this established model, we propose experiments to conduct a comprehensive study on CAR T cell memory that will investigate CAR T cell differentiation into distinct subsets and protection from tumor relapse. CAR T cell memory will be studied in the context of immunologically distinct solid tumors and will concurrently assess the impacts of some clinical strategies to enhance CAR T cell immunotherapy on CD8 CAR T cell memory generation. In the second aim of this proposal, we will test our hypothesis that ectopic expression of a gene that promotes both CD8 T cell memory differentiation and effector T cell survival will enhance the overall outcome of CAR T cell therapy. By incorporating this gene into our existing CAR, we will test this hypothesis using a 4th generation CAR and investigate the impacts of constitutive expression of a pro-memory gene in CAR T cell function and memory. The research and training in this proposal will be conducted at Seattle Children’s Research Institute (SCRI) which is among the top ranked centers for pediatric cancer research, and a member of the Seattle Cancer Care Alliance. Training will be performed under the close mentorship of top experts in the field of T cell immunology Drs. Vandana Kalia and Surojit Sarkar, with additional support from leaders in the field of cancer immunotherapy: Drs. Mac Cheever, Mike Jensen, and Cam Turtle. Additional postdoctoral training will be provided through seminars, presentations, workshops, and classes dedicated to postdoctoral training provided by SCRI, The University of Washington, and Fred Hutchinson Cancer Research Center.

项目概要/摘要 CAR T细胞免疫疗法在液体肿瘤的早期控制中显示出越来越大的成功， B细胞急性淋巴细胞白血病（B-ALL）、B细胞淋巴瘤和多发性骨髓瘤。然而，在这方面， 建立CAR T细胞介导的长期保护已被证明具有挑战性，肿瘤复发发生在 大约30-50%的患者对CAR T细胞治疗显示出初步反应。在许多临床试验中， 肿瘤抗原（+）复发占总复发病例的大多数，表明CAR 这些患者的T细胞未能灌输长期的肿瘤控制和防止肿瘤复发的保护作用。 与CAR T细胞治疗临床试验中观察到的趋势一致，我们实验室的初步数据来自 一种实体瘤模型，揭示了肿瘤复发与肿瘤复发的数量之间的显著负相关性。 在复发时检测到的CAR T细胞。因此，我们假设有效的CAR T细胞记忆是至关重要的， 长期保护肿瘤抗原（+）复发。尽管人们普遍认为 由于相关临床前模型的局限性，CAR T细胞研究领域缺乏 直接解决CAR T细胞记忆的全面研究。 追求我们的长期目标，开发增强CAR T细胞功能和记忆的方法。 第三代，我们已经开发了一种涉及小鼠第三代CAR T细胞的实体瘤模型， 免疫活性小鼠和不同的协同肿瘤细胞系。利用这个模型，我们提出 实验对CAR T细胞记忆进行全面研究， 分化成不同的亚群和防止肿瘤复发。CAR T细胞记忆将在 免疫学上不同的实体瘤的背景下，并将同时评估一些临床的影响， 增强CAR T细胞免疫疗法对CD 8 CAR T细胞记忆生成的策略。在第二个目标中 这个建议，我们将测试我们的假设，异位表达的基因，促进CD 8 T细胞 记忆分化和效应T细胞存活将增强CAR T细胞疗法的总体结果。通过 将该基因整合到我们现有的CAR中，我们将使用第四代CAR来测试这一假设， 研究前记忆基因的组成型表达对CAR T细胞功能和记忆的影响。 本提案中的研究和培训将在西雅图儿童研究所进行 （SCRI）是儿科癌症研究的顶级中心之一，也是西雅图的成员 癌症护理联盟。培训将在T细胞领域顶级专家的密切指导下进行 免疫学Vandana卡利亚和Surojit Sarkar博士，以及癌症领域领导者的额外支持 免疫疗法：Mac Cheever博士，Mike詹森博士和Cam Turtle博士。更多博士后培训将在 通过研讨会、演讲、讲习班和专门用于博士后培训的课程提供 由SCRI，华盛顿大学和弗雷德哈钦森癌症研究中心。