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.

该提案包括职业发展计划和研究计划，将为Mullinax博士提供 专业知识和必要的数据，以实现他的长期职业目标，成为一个独立的外科医生- 科学家该计划中确定的短期职业目标包括发展早期管理方面的专业知识， 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保持一致，以确保 在此奖项期间，利用莫菲特癌症中心的机构实力， 他的导师在细胞免疫疗法方面的科学专业知识。 本提案中包含的临床试验是基于Mullinax博士已完成的临床前工作。 在过去的三年里，从外科肿瘤学的奖学金加入教师。他的工作重点是 从软组织肉瘤（STS）扩增肿瘤浸润淋巴细胞（TIL）的方法。示威后 扩大肿瘤反应性TIL的可行性，过继细胞治疗（ACT）的基本要求， 完成了FDA研究性新药（IND）申请，制定了临床试验方案，并获得了 启动资金。随着这些努力的成功，他现在是一项临床试验的首席研究员， 将评估ACT在转移性STS患者中的安全性和可行性。 他提出的科学工作包括对肿瘤和T细胞之间相互作用的更深入研究 在STS STS的分子发病机制与大多数上皮性肿瘤不同， 变异或相互染色体易位导致间充质组织的肿瘤发生， 与常见于上皮恶性肿瘤的点突变有关。Mullinax博士概述了一个工作范围 这将利用生物信息学分析来了解基因组不稳定性与基因组之间的关系。 从STS扩展TIL。他还将完成实验，以了解T细胞的肿瘤特异性活性， 细胞亚群，特别是组织驻留记忆（TRM）T细胞，作为选择最佳克隆的方法， 在ACT临床试验中向患者递送的细胞输注产品的扩展。 这项工作的完成将由他的主要导师Shari Pilon-Thomas博士和合作伙伴密切监督。 导师James J Mulé博士他将每周与他的主要导师会面，每两周与他的临床试验会面 顾问（达蒙里德，医学博士和阿莫德Sarnaik医学博士），并与他的完整的咨询委员会， Jose Conejo-Garcia（医学博士、博士）和Jamie Teer（博士）也加入了上述教师队伍。他描述了一个严格的 教学课程工作的时间表，以解决培训的伦理试验设计，赠款写作，和生物统计学。 这项工作的完成将使Mullinax博士能够在本年度的倒数第二年提交R 01 授予并确保进行早期临床试验所需的专业知识， 他在临床实践中治疗的STS患者的治疗选择。