The importance of CD4+ tumor-infiltrating lymphocytes (TIL) in adoptive cell transfer

CD4 肿瘤浸润淋巴细胞 (TIL) 在过继细胞移植中的重要性

• 批准号: 10348653
• 负责人: MacLean Hall
• 金额: $ 3.95万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348653
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Antigen-Presenting Cells; Antigens; Antitumor Response; Autologous Tumor-Infiltrating Lymphocyte; Basic Science; Bioinformatics; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cancer Center; Cancer Patient; Cells; Cholangiocarcinoma; Clinic; Clinical; Clinical Trials; Complex; Data Analyses; Development; Dipeptidyl-Peptidase IV; Disease; ERBB2IP gene; Educational workshop; Effectiveness; Experimental Designs; Fostering; Goals; Grant; Human; Immunology; Immunology procedure; Immunotherapeutic agent; Immunotherapy; In Vitro; Infusion procedures; Institution; Interferon Type II; Investigation; Lead; MHC Class I Genes; MHC Class II Genes; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Manuscripts; Mediating; Mediator of activation protein; Mentors; Mentorship; Metastatic Melanoma; Metastatic to; Methodology; Methods; Modeling; Molecular Biology; Mus; Nature; Oral; PD-1 blockade; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Population; Postdoctoral Fellow; Production; Property; Refractory; Reporting; Research; Research Institute; Research Personnel; Resistance; Resistance development; Role; Sampling; Source; Specificity; Specimen; System; T cell response; T memory cell; T-Lymphocyte; Techniques; Testing; Therapeutic; Training; Training Programs; Transgenic Organisms; Translational Research; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Writing; anti-PD-1; anticancer research; antigen processing; base; cancer immunotherapy; career; career development; cell killing; clinical application; clinical efficacy; clinically relevant; cytokine; cytotoxic; doctoral student; efficacy evaluation; human model; immune checkpoint blockade; immunogenicity; improved; in vivo; insight; lymphocyte product; malignant breast neoplasm; meetings; melanoma; member; mouse model; neoantigens; neoplastic cell; novel; novel strategies; objective response rate; patient derived xenograft model; patient population; pre-clinical; resistance mechanism; response; skills; stemness; symposium; targeted cancer therapy; trend; tumor; tumor immunology

Project Summary/Abstract Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TIL) is a promising therapeutic option for cancer patients, demonstrating a 30-55% objective response rate in clinical trials with metastatic melanoma patients. Current strategies for TIL production are CD8+ T cell-centric, despite indications that CD4+ T cells are prevalent across multiple malignancies, are polyfunctional in nature, and provide therapeutic benefit in a multitude of clinical and pre-clinical applications. The overall objective of this proposal is to systematically investigate the role of CD4+ TIL in the settings of ACT and immunotherapeutic resistance. We hypothesize that CD4+ TIL are instrumental to the effectiveness of ACT and provide an effective mechanism to overcome resistance to current immunotherapy strategies. To investigate this hypothesis, we will 1) Determine the function and phenotype of CD4+ TIL from human melanoma samples, 2) Elucidate the mechanisms of the CD4+ TIL anti-tumor response in vivo, and 3) Examine the contribution of CD4+ TIL in overcoming resistance to immunotherapy. In Aim 1, this study will determine and validate the intrinsic determinants of CD4+ TIL that provide clinical efficacy through the use of in vitro immunologic assays and bioinformatics analysis based on de-identified samples from patients who received ACT with TIL. Aim 2 will approach the mechanism underlying in vivo efficacy through the use of mouse models to address unanswered questions of antigen specificity and antigen recognition by CD4+ T cells. Finally, Aim 3 will utilize complex murine and human systems, including CRISPR/Cas9, to investigate the use of CD4+ TIL to rescue resistance to immunotherapy. The results of this study will provide rationale for the inclusion of CD4+ T cells in TIL products for ACT, especially in the setting of immunotherapeutic resistance. Through the completion of these aims, MacLean will undergo an intensive training in advanced immunology and fundamental principles in bioinformatics and molecular biology that will prepare him for a successful career as an independent investigator. This training is fully supported by his mentor, Dr. Shari Pilon-Thomas, collaborator, Dr. Amod Sarnaik, mentorship committee and the institution, Moffitt Cancer Center and Research Institute. The objective of this training program is to foster the career development of MacLean in basic and translational research through mentorship in 1) tumor immunology and murine models, 2) data analysis and interpretation, 3) oral presentation skills, 4) scientific writing skills, and 5) participation in scientific meetings. Drs. Pilon-Thomas and Sarnaik will meet with MacLean weekly to provide guidance on experimental design and to discuss data analysis and interpretation. MacLean will also meet with members of his mentorship committee on a quarterly basis for valuable added insight into the progress of his project. MacLean will actively participate in advanced courses in immunology, attend national conferences and grant writing workshops, and prepare manuscripts with the overall goal of transitioning from Ph.D. student to postdoctoral fellow and ultimately an independent investigator in translational academic research.

项目总结/摘要 用肿瘤浸润淋巴细胞（TIL）进行连续性细胞转移（ACT）是一种有前途的治疗选择， 癌症患者，在转移性黑色素瘤临床试验中显示出30-55%的客观缓解率 患者目前的TIL产生策略是以CD 8 + T细胞为中心的，尽管有迹象表明，CD 4 + T细胞 在多种恶性肿瘤中普遍存在，本质上是多功能的，并在 大量的临床和临床前应用。本建议的总体目标是系统地 研究CD 4 + TIL在ACT和免疫治疗耐药性背景下的作用。我们假设 CD 4 + TIL有助于ACT的有效性，并提供了一种有效的机制， 对当前免疫治疗策略的抵抗。为了研究这个假设，我们将1）确定 2）阐明CD_4 ~+淋巴细胞的功能和表型， 体内CD 4 + TIL抗肿瘤反应，以及3）检查CD 4 + TIL在克服抗性中的贡献 免疫疗法在目的1中，本研究将确定并验证CD 4 + TIL的内在决定因素， 通过使用体外免疫测定和基于以下的生物信息学分析提供临床疗效： 来自接受ACT和TIL的患者的去识别样本。目标2将探讨 通过使用小鼠模型来解决抗原特异性的未回答的问题的体内功效， CD 4 + T细胞的抗原识别。最后，目标3将利用复杂的鼠和人类系统，包括 CRISPR/Cas9，以研究使用CD 4 + TIL来挽救对免疫疗法的抗性。的结果 研究将为ACT的TIL产品中包含CD 4 + T细胞提供依据，尤其是在以下情况下 免疫抵抗通过完成这些目标，麦克莱恩将经历一个密集的 在先进的免疫学和生物信息学和分子生物学的基本原则，将 为他成为一名成功的独立调查员做好准备。这项培训得到了他的全力支持。 导师Shari Pilon-Thomas博士，合作者阿莫德Sarnaik博士，导师委员会和机构， 莫菲特癌症中心和研究所。该培训计划的目标是培养 麦克莱恩在基础和转化研究的发展，通过在1）肿瘤免疫学和 鼠模型，2）数据分析和解释，3）口头陈述技能，4）科学写作技能，和5） 参加科学会议。Pilon-Thomas博士和Sarnaik博士将每周与MacLean会面， 指导实验设计并讨论数据分析和解释。麦克莱恩还将会见 他的导师委员会成员每季度为宝贵的增加洞察他的进展， 项目麦克莱恩将积极参加免疫学高级课程，参加全国会议， 授予写作研讨会，并准备手稿的总体目标是从博士学位过渡。学生 博士后研究员，并最终成为翻译学术研究的独立调查员。