Leveraging the Lymphocytic Infiltration of Soft Tissue Sarcoma for Autologous Cellular Immunotherapy

利用软组织肉瘤的淋巴细胞浸润进行自体细胞免疫治疗

• 批准号: 10038950
• 负责人: John Mullinax
• 金额: $ 24.53万
• 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: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10038950
• 关键词: Address; Adoptive Cell Transfers; Advisory Committees; Antitumor Response; Autologous; Award; Bioinformatics; Biological Assay; Biometry; CD8-Positive T-Lymphocytes; Cancer Center; Cells; Cellular immunotherapy; Cervical; Cessation of life; Childhood; Chromosomal translocation; Clinical; Clinical Trials; Clinical Trials Design; Clinical trial protocol document; Clonal Expansion; Coculture Techniques; Copy Number Polymorphism; Data; Development Plans; Diagnosis; Digestion; Doctor of Philosophy; Dose; Ensure; Epithelial; Epithelium; Equine mule; Ethics; Event; Faculty; Fellowship; Funding; Genomic Instability; Genomics; Goals; Grant; Histologic; Immunobiology; In complete remission; Infiltration; Infusion procedures; Institution; Interferon Type II; Interleukin-2; Investigation; Investigational New Drug Application; Investigational Therapies; Laboratories; Laboratory Finding; Laboratory Research; Life; Literature; Lung; Lymphocyte; Lymphocyte Subtypings; Malignant Neoplasms; Measures; Mechanics; Memory; Mentors; Mesenchymal; Metastatic Melanoma; Metastatic to; Methods; Molecular; Mutation; Operating Rooms; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Phase I Clinical Trials; Point Mutation; Population; Positioning Attribute; Principal Investigator; Probability; Refractory Disease; Regimen; Resected; Role; Safety; Schedule; Scientist; Soft tissue sarcoma; Solid Neoplasm; Specimen; Surgeon; Surgical Oncology; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapy Clinical Trials; Tissues; Training; Translating; Tumor Expansion; Tumor-Associated Process; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Work; Writing; adaptive immune response; age group; base; career; career development; clinical practice; early phase clinical trial; experimental study; falls; genomic data; improved; in silico; lymphocyte product; melanoma; neoplastic cell; novel; phase I trial; pre-clinical; primary endpoint; research and development; response; safety and feasibility; safety testing; sarcoma; secondary endpoint; standard care; trial design; tumor; tumor growth; tumorigenesis; young adult

This proposal includes a career development plan and research plan that will provide Dr. Mullinax with the expertise and data necessary to reach his long-term career goal of becoming an independent surgeon- scientist. The short-term career goals identified in this plan include developing expertise in the conduct of early phase clinical trials, the bioinformatics analysis of genomic datasets, and the immunobiology of T-cell subsets present in soft tissue sarcoma. The career development plan and scientific aims are in alignment to ensure efficient progress during this award, leveraging both the institutional strength of Moffitt Cancer Center and scientific expertise of his mentors in the delivery of cellular immunotherapy. The clinical trial included on this proposal is based on the preclinical work that Dr. Mullinax has completed over the past three years since joining the faculty from fellowship in surgical oncology. His work has focused on methods to expand tumor infiltrating lymphocytes (TIL) from soft tissue sarcoma (STS). After demonstrating the feasibility of expanding tumor-reactive TIL, a fundamental requirement for adoptive cell therapy (ACT), he completed an FDA investigational new drug (IND) application, developed a clinical trial protocol, and obtained funding for activation. With these efforts successful, he is now the principal investigator of a clinical trial which will assess the safety and feasibility of ACT in patients with metastatic STS. The scientific work he has proposed includes a deeper study of the interaction between the tumor and T-cells within STS. The molecular pathogenesis of STS is different than most epithelial tumors where copy number variation or reciprocal chromosomal translocation results in oncogenesis of mesenchymal tissue, as opposed to the point mutations commonly seen in epithelial malignancies. Dr. Mullinax has outlined a scope of work that will utilize bioinformatics analysis to understand the relationship between genomic instability and the expansion of TIL from STS. He will also complete experiments to understand the tumor-specific activity of T- cell subsets, specifically tissue resident memory (TRM) T-cells, as a method of selecting optimal clonal expansion in the cellular infusion product delivered to patients in ACT clinical trials. Completion of this work will be overseen closely by his primary mentor Shari Pilon-Thomas, PhD and co- mentor James J Mulé, PhD. He will meet weekly with his primary mentor, bi-weekly with his clinical trial advisors (Damon Reed, MD and Amod Sarnaik MD), and quarterly with his complete advisory committee which adds Jose Conejo-Garcia, MD, PhD and Jamie Teer, PhD to the above faculty. He has described a rigorous schedule of didactic course work to address training the ethics of trial design, grant writing, and biostatistics. Completion of this work will position Dr. Mullinax well for R01 submission during the penultimate year of this award and ensure the expertise needed to conduct early phase clinical trials which translate the findings of his laboratory to therapeutic options for the STS patients that he treats in his clinical practice.

该建议包括一项职业发展计划和研究计划，该计划将为Mullinax博士提供 实现他成为独立外科医生的长期职业目标所必需的专业知识和数据 - 科学家。该计划中确定的短期职业目标包括在早期进行专业知识 阶段临床试验，基因组数据集的生物信息学分析以及T细胞亚群的免疫生物学 存在于软组织肉瘤中。职业发展计划和科学目标是一致的，以确保 在此奖励期间有效进步，利用莫菲特癌症中心的机构实力和 他的导师在提供细胞免疫疗法方面的科学专业知识。 该提案中包括的临床试验是基于Mullinax博士完成的临床前工作 自从手术肿瘤学研究员加入教职员工以来的过去三年。他的工作集中于 从软组织肉瘤（STS）扩展肿瘤浸润淋巴细胞（TIL）的方法。演示后 扩大肿瘤反应性TIL的可行性，这是适应性细胞疗法（ACT）的基本要求（ACT） 完成了FDA研究新药（IND）应用，制定了临床试验方案，并获得了 激活资金。通过这些努力成功，他现在是一项临床试验的主要研究者 将评估转移性ST患者ACT的安全性和可行性。 他提出的科学工作包括对肿瘤与T细胞之间相互作用的更深入研究 在STS内。 ST的分子发病机理与大多数拷贝数的大多数上皮肿瘤不同 变异或相互的染色体易位会导致间充质组织的肿瘤发生，而不是相反 到上皮恶性肿瘤中常见的点突变。 Mullinax博士概述了工作范围 这将利用生物信息学分析来了解基因组不稳定性与 TIL从STS扩展。他还将完成实验，以了解T-的肿瘤特异性活性 细胞子集，特别是组织居民记忆（TRM）T细胞，作为选择最佳克隆的一种方法 在ACT临床试验中递送给患者的细胞输注产品的扩展。 这项工作的完成将由他的主要精神莎莉·皮隆·托马斯（Pilon-Thomas），博士和合作 导师JamesJMulé博士。他将每周与他的主要导师见面，每两周与他的临床试验见面 顾问（Damon Reed，医学博士和Amod Sarnaik MD），以及他的完整咨询委员会季刊 在上述教师中，将Jose Conejo-Garcia，医学博士和Jamie Teer和Jamie Teer添加到了。他描述了一个严格的 教学课程的时间表旨在解决培训试验设计，赠款写作和生物统计学的道德规范。 这项工作的完成将使Mullinax博士在倒数第二年中适合R01提交 授予并确保进行早期临床试验所需的专业知识，以转化其发现 他在临床实践中治疗的STS患者的治疗选择实验室。