Immunology

免疫学

基本信息

批准号：
10115694
负责人：
Jose R Conejo-Garcia
金额：
$ 5.68万
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：
1998
资助国家：
美国
起止时间：
1998-02-18 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115694
关键词：
Address Adoptive Cell Transfers Adoptive Transfer Agreement Allogenic Antitumor Response Area Cancer Center Cancer Center Support Grant Cancer Patient Cell Therapy Cells Clinical Clinical Immunology Clinical Services Clinical Trials Collaborations Core Facility Cytotoxic T-Lymphocytes Effector Cell Faculty Funding Gene Expression Profile Goals Grant Hematologic Neoplasms Hematopoietic Neoplasms Histone Deacetylase Inhibitor Human Immune Immune checkpoint inhibitor Immune response Immune system Immunology Immunotherapeutic agent Immunotherapy Industry Infrastructure Interleukin-12 Interruption Intervention Intervention Trial Investments JAK2 gene Laboratory Study Malignant Neoplasms Minor Histocompatibility Antigens Molecular Myeloid-derived suppressor cells NCI-Designated Cancer Center Natural Immunity Natural Killer Cells Patients Peer Review Process Publications Publishing Regulatory T-Lymphocyte Reporting Research Research Personnel Role STAT3 gene Scientist Severities Severity of illness Solid Neoplasm Source T cell response T cell therapy T-Lymphocyte Therapeutic Translating Translations Transplantation Tumor Immunity Tumor-Infiltrating Lymphocytes Vaccination adaptive immunity bench to bedside cancer immunotherapy cohesion cost disorder prevention graft vs host disease graft vs leukemia effect hematopoietic cell transplantation immunoregulation immunotherapy clinical trials immunotherapy trials improved innovation instructor inter-institutional interleukin 9 receptor interleukin-23 leukemia member neoplastic cell novel preclinical study preservation prevent programs recruit response restoration small molecule success tumor working group

项目摘要

PROJECT SUMMARY The overall goal of the Moffitt Cancer Center (MCC) Immunology (IMM) Program is to define the mechanisms by which tumors evade rejection by the immune system and to develop strategies to thwart them. Fundamental discoveries by IMM members have led to novel immunotherapy trials that directly benefit cancer patients. Key to the Program's success is the close integration of IMM clinical, translational, and basic scientists that facilitates rapid progression of novel immunotherapies from the bench to bedside. The goals of Specific Aim 1 are to advance and translate T-cell therapies for solid tumors and hematologic malignancies, by bringing laboratory and pre-clinical studies of the IMM Program to the patient bedside in the form of novel investigator- initiated clinical trials. Specific areas of focus include: (1) adoptive T-cell immunotherapy using ex vivo expanded tumor-infiltrating lymphocytes and genetically modified immune effector cells; (2) mechanistic strategies to improve adoptive cell therapy; (3) restoration of tumor-specific responses by immune checkpoint inhibitors, histone deacetylase inhibitors (HDACi), and vaccination; and (4) defining gene expression signatures of immune responders. MCC infrastructure that supports IMM members includes: (i) the Immunotherapy Working Group that conceives interventional trials; (ii) a Good Manufacturing Practice- compliant Cellular Therapy Core Facility; and (iii) the interdisciplinary Immune and Cellular Therapy clinical service to deliver therapy to patients. The goals of Specific Aim 2 are to define molecular and cellular mechanisms that can exploit innate and adaptive immunity against cancer. Here, IMM members seek to discover and develop molecular approaches to harness the immune system. Collaborative studies include those assessing T-cell recruitment and suppression, natural killer cell control, myeloid-derived suppressor cell expansion, and selective HDACi immune modulation. These initiatives have generated several innovative approaches that control these processes, including therapeutic translation into clinical trials. The goals of Specific Aim 3 are to prevent graft-versus-host disease (GVHD) while maintaining the potency of graft-versus- leukemia and other blood cancers following hematopoietic cell transplantation (HCT). The IMM Program has made significant impact in this arena, including the discovery that Th17 cells have a central role in the severity of GVHD and in the response to therapy. The approaches to prevent GVHD and maintain anti-tumor response include: (1) adoptive transfer of donor Tregs specific against host minor-histocompatibility antigens; (2) targeting the common IL-12/IL-23 p40 receptor chain; (3) targeting JAK2 or STAT3; and (4) defining gene expression signatures associated with operational tolerance following allogeneic HCT. The Program is composed of 25 members from 10 different academic departments. During the reporting period, 534 cancer- related articles were published, with 167 (31)% intra-programmatic and 207 (39%) inter-programmatic. Grant funding for the Program is $18.8 million, of which $7.0 million is peer-reviewed , including 43% from NCI.

项目概要莫菲特癌症中心 (MCC) 免疫学 (IMM) 计划的总体目标是定义机制肿瘤通过免疫系统逃避排斥并制定阻止它们的策略。基本的 IMM 成员的发现催生了新的免疫疗法试验，可直接使癌症患者受益。钥匙该计划的成功在于 IMM 临床、转化和基础科学家的紧密结合，促进新型免疫疗法从实验室到临床的快速进展。具体目标 1 的目标旨在推进和转化实体瘤和血液恶性肿瘤的 T 细胞疗法，通过 IMM 计划的实验室和临床前研究以新型研究者的形式在患者床边进行启动了临床试验。具体重点领域包括：(1) 使用离体的过继性 T 细胞免疫治疗扩大肿瘤浸润淋巴细胞和转基因免疫效应细胞； (2)机械性改善过继性细胞疗法的策略； (3)通过免疫检查点恢复肿瘤特异性反应抑制剂、组蛋白脱乙酰酶抑制剂 (HDACi) 和疫苗接种； (4) 定义基因表达免疫反应者的签名。支持 IMM 成员的 MCC 基础设施包括：(i) 构思介入试验的免疫治疗工作组； (ii) 良好生产规范 - 合规的细胞治疗核心设施； (iii) 跨学科免疫和细胞治疗临床为患者提供治疗的服务。具体目标 2 的目标是定义分子和细胞可以利用先天性和适应性免疫来对抗癌症的机制。在这里，IMM 成员寻求发现和开发利用免疫系统的分子方法。合作研究包括评估 T 细胞招募和抑制、自然杀伤细胞控制、骨髓源性抑制细胞扩展和选择性 HDACi 免疫调节。这些举措产生了多项创新控制这些过程的方法，包括将治疗转化为临床试验。的目标具体目标 3 是预防移植物抗宿主病 (GVHD)，同时保持移植物抗宿主病的效力造血细胞移植（HCT）后的白血病和其他血癌。 IMM 计划有在此领域产生了重大影响，包括发现 Th17 细胞在严重程度中起着核心作用 GVHD 和对治疗的反应。预防GVHD和维持抗肿瘤反应的方法包括：（1）对宿主次要组织相容性抗原具有特异性的供体Treg的过继转移； (2) 靶向共同的 IL-12/IL-23 p40 受体链； (3)靶向JAK2或STAT3； (4)定义基因与同种异体 HCT 后的操作耐受性相关的表达特征。该计划是由来自10个不同学术部门的25名成员组成。报告期内，534 名癌症患者发表了相关文章，其中 167 (31)% 属于程序内文章，207 (39%) 属于程序间文章。授予为计划金额 1880 万美元，其中 700 万美元用于同行评审，其中 43% 来自 NCI。