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.

项目摘要/摘要 具有肿瘤浸润淋巴细胞（TIL）的收养细胞转移（ACT）是有前途的治疗选择 癌症患者，在转移性黑色素瘤的临床试验中证明了30-55％的客观反应率 患者。尽管有迹象表明CD4+ T细胞，但目前的TIL生产策略以CD8+ T细胞为中心 在多种恶性肿瘤中普遍存在，本质上是多功能的，并在 众多临床和临床前应用。该提案的总体目的是系统地 研究CD4+ TIL在ACT和免疫治疗抗性环境中的作用。我们假设 CD4+ TIL对ACT的有效性有用，并提供了一种有效的机制来克服 抵抗当前的免疫疗法策略。为了研究这一假设，我们将确定 来自人类黑色素瘤样品的CD4+ TIL的功能和表型，2）阐明 CD4+ TIL抗肿瘤反应在体内和3）检查CD4+ TIL在克服电阻中的贡献 进行免疫疗法。在AIM 1中，这项研究将确定并验证CD4+ TIL的固有决定因素 通过使用基于体外免疫学分析和基于生物信息学分析的体外免疫学分析来提供临床功效 从收到TIL ACT的患者中取消识别样品。 AIM 2将接近基础机制 通过使用鼠标模型来解决抗原特异性和 CD4+ T细胞的抗原识别。最后，AIM 3将利用复杂的鼠和人类系统，包括 CRISPR/CAS9，研究CD4+ TIL的使用来挽救对免疫疗法的抗性。结果的结果 研究将为将CD4+ T细胞纳入TIL产品提供基本原理，尤其是在 免疫治疗性抗性。通过完成这些目标，麦克林将经历密集的 对生物信息学和分子生物学的高级免疫学和基本原理的培训 为他作为独立调查员的成功事业做好准备。这项培训得到了他的完全支持 导师，Shari Pilon-Thomas博士，合作者，Amod Sarnaik博士，指导委员会和机构，机构， 莫菲特癌症中心和研究所。该培训计划的目的是促进职业 通过指导1）肿瘤免疫学和转化研究中的麦克林研究 鼠模型，2）数据分析和解释，3）口头表现技巧，4）科学写作技巧和5） 参加科学会议。博士。 Pilon-Thomas和Sarnaik将与MacLean Weekly见面以提供 实验设计指南并讨论数据分析和解释。麦克林也将与 他的指导委员会成员每季度获得宝贵的洞察力，以增加对他的进步的了解 项目。麦克林将积极参加免疫学高级课程，参加民族会议和 授予写作讲习班，并准备从博士学位过渡的总体目标的手稿。学生 博士后研究员，最终是翻译学术研究的独立研究者。