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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

基本信息

批准号：
10689135
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
项目类别：
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/10689135
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 Clonal Expansion Coculture Techniques Copy Number Polymorphism Data Development Plans Diagnosis Digestion Doctor of Philosophy Dose Ensure Epithelium Equine mule Ethics Event Faculty Fellowship Funding Genomic Instability Genomics Goals Grant Histologic Immunobiology In complete remission Infusion procedures Institution Interferon Type II Interleukin-2 Investigation Investigational New Drug Application Investigational Therapies Laboratories Laboratory Finding Laboratory Research Life Literature Lung Lymphocyte Subtypings Lymphocytic Infiltrate Malignant Neoplasms Measures Mechanics Memory Mentors Mesenchymal Metastatic Melanoma Methods Molecular Mutation Operating Rooms Outcome Pathogenesis Pathologic Pathology Patient Selection 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 cell infiltration T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Therapy Clinical Trials Tissues Training Translating Tumor Expansion Tumor-Associated Process Tumor-Infiltrating Lymphocytes Work Writing adaptive immune response age group career career development clinical practice clinical trial protocol early phase clinical trial experimental study falls genomic data immune cell infiltrate improved in silico lymphocyte product melanoma novel phase I trial pre-clinical primary endpoint productivity loss research and development response safety and feasibility safety assessment safety testing sarcoma secondary endpoint standard care tissue resident memory T cell trial design tumor tumor growth tumorigenesis young adult

项目摘要

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，将为穆利纳克斯博士提供达到他成为一名独立外科医生的长期职业目标所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开展阶段临床试验、基因组数据集的生物信息学分析和T细胞亚群的免疫生物学出现在软组织肉瘤中。职业发展计划和科学目标保持一致，以确保在这个奖项期间取得了有效的进展，利用了莫菲特癌症中心的机构力量和他的导师在提供细胞免疫疗法方面的科学专业知识。该提案中包含的临床试验是基于穆利纳克斯博士已经完成的临床前工作。在过去的三年里，他从外科肿瘤学的奖学金中加入了教职。他的工作重点是方法从软组织肉瘤组织中扩增肿瘤浸润性淋巴细胞(TIL)。在演示之后扩大肿瘤反应性TIL的可行性，这是过继细胞治疗(ACT)的基本要求完成FDA研究新药(IND)申请，开发临床试验方案，并获得为激活提供资金。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更深入地研究肿瘤和T细胞之间的相互作用在STS内部。STS的分子发病机制不同于大多数上皮性肿瘤变异或染色体易位导致间充质组织的肿瘤发生，而不是达到在上皮性恶性肿瘤中常见的点突变。穆利纳克斯博士概述了一项工作范围这将利用生物信息学分析来理解基因组不稳定性和 TIL由STS扩展而来。他还将完成实验，以了解T-T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临床试验中提供给患者的细胞输液产品的扩展。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詹姆斯·J·穆勒博士。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(Damon Reed，MD和Amod Sarnaik MD)，并每季度与他的完整咨询委员会在上述教职员工中增加了何塞·科内霍-加西亚博士和杰米·蒂尔博士。他描述了一种严格的教学课程工作时间表，旨在解决试验设计、拨款撰写和生物统计学方面的道德培训问题。这项工作的完成将使Mullinax博士很好地在今年倒数第二年提交R01 授予并确保进行早期临床试验所需的专业知识，这些试验将HIS的发现转化为为他在临床实践中治疗的STS患者提供实验室到治疗选择。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Management of Primary Retroperitoneal Sarcoma (RPS) in the Adult: An Updated Consensus Approach from the Transatlantic Australasian RPS Working Group.

成人中主要腹膜后肉瘤（RPS）的管理：跨大西洋澳大利亚RPS工作组的更新共识方法。

DOI：
10.1245/s10434-021-09654-z
发表时间：
2021-11
期刊：
ANNALS OF SURGICAL ONCOLOGY
影响因子：
3.7
作者：
Swallow, Carol J.;Strauss, Dirk C.;Bonvalot, Sylvie;Rutkowski, Piotr;Desai, Anant;Gladdy, Rebecca A.;Gonzalez, Ricardo;Gyorki, David E.;Fairweather, Mark;van Houdt, Winan J.;Stoeckle, Eberhard;Park, Jae Berm;Albertsmeier, Markus;Nessim, Carolyn;Cardona, Kenneth;Fiore, Marco;Hayes, Andrew;Tzanis, Dimitri;Skoczylas, Jacek;Ford, Samuel J.;Ng, Deanna;Mullinax, John E.;Snow, Hayden;Haas, Rick L.;Callegaro, Dario;Smith, Myles J.;Bouhadiba, Toufik;Stacchiotti, Silvia;Jones, Robin L.;DeLaney, Thomas;Roland, Christina L.;Raut, Chandrajit P.;Gronchi, Alessandro
通讯作者：
Gronchi, Alessandro

Surgical Considerations for Tumor Tissue Procurement to Obtain Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy.

肿瘤组织采购的手术考虑因素，以获得肿瘤浸润的淋巴细胞以进行继发性细胞疗法。