Immunology

免疫学

基本信息

批准号：
10230164
负责人：
Jose R Conejo-Garcia
金额：
$ 0.45万
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/10230164
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.

项目摘要莫菲特癌症中心（MCC）免疫学（IMM）计划的总体目标是定义机制通过哪种肿瘤逃避免疫系统的排斥，并制定策略挫败它们。基本的 IMM成员的发现导致了新的免疫疗法试验，这些试验直接使癌症患者受益。钥匙该计划的成功是IMM临床，转化和基本科学家的密切整合，促进新型免疫疗法从长凳到床边的快速发展。特定目标的目标1 通过带来的，用于实体瘤和血液系统恶性肿瘤的T细胞疗法 IMM计划对患者床边的实验室和临床前研究以新型研究者的形式形式开始的临床试验。重点的特定领域包括：（1）使用离体的产物T细胞免疫疗法扩展的肿瘤浸润淋巴细胞和转基因的免疫效应细胞；（2）机械改善收养细胞疗法的策略；（3）免疫检查点恢复肿瘤特异性反应抑制剂，组蛋白脱乙酰基酶抑制剂（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基础架构包括：（i）构想介入介入试验的免疫疗法工作组；（ii）良好的制造实践 - 兼容的蜂窝疗法核心设施；（iii）跨学科免疫和细胞疗法临床为患者提供治疗的服务。特定目标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对癌症的机制。在这里，IMM成员试图发现并开发分子方法来利用免疫系统。协作研究包括那些评估T细胞募集和抑制，天然杀伤细胞控制，髓样衍生的抑制细胞的人扩展和选择性HDACI免疫调节。这些举措产生了一些创新方法控制这些过程，包括治疗转化为临床试验。目标具体目的3是防止移植物抗宿主病（GVHD），同时保持移植物的效力 - 造血细胞移植后（HCT）后白血病和其他血液癌。 IMM计划有在该领域产生了重大影响，包括发现Th17细胞在严重程度中具有核心作用 GVHD和对治疗的反应。防止GVHD并保持抗肿瘤反应的方法包括：（1）针对宿主较小的兼容性抗原特异性供体Tregs的收养转移；（2）靶向常见的IL-12/IL-23 P40受体链；（3）针对JAK2或STAT3；（4）定义基因同种异体HCT后与操作耐受性相关的表达特征。该程序是由来自10个不同学术部门的25名成员组成。在报告期间，有534个癌症 - 相关文章发表了，有167（31）％的前编程和207（39％）。授予资助计划为1,880万美元，其中700万美元接受了同行评审，包括NCI的43％。