Therapeutic antitumor and antiviral potential of allogeneic gamma-delta T cells

同种异体 γ-δ T 细胞的治疗性抗肿瘤和抗病毒潜力

基本信息

批准号：
8143384
负责人：
RICHARD D LOPEZ
金额：
$ 18.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143384
关键词：
Accounting Address Adoptive Immunotherapy Adoptive Transfer Allogenic Animal Model Animals Antigens Antiviral Agents Autoantigens Autologous Award Biological Biological Models Blood Cells Bone Marrow C57BL/6 Mouse Cancer Patient Cell Therapy Cells Chimerism Clinical Clinical Trials Clinical Trials Design Communicable Diseases Cyclophosphamide Defect Derivation procedure Development Disease Disease Progression Donor Lymphocyte Infusion Dose Engraftment Epithelial Exploratory/Developmental Grant First Degree Relative Funding Funding Mechanisms Generations Generic Drugs Graft Rejection Grant Growth HLA Antigens Hematopoiesis Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Human Herpesvirus 4 Human Papillomavirus Immune response Immunologic Monitoring Immunotherapy Inbred BALB C Mice Individual Infection Infusion procedures Low Dose Radiation Lymphoma Major Histocompatibility Complex Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of prostate Mammary Neoplasms Measurable Mediating Mind Minority Modeling Monitor Morbidity - disease rate Mouse Strains Mus Nasopharynx Carcinoma Oncogenic Viruses Parents Patients Peptides Persons Phase Process Property Radiation Recovery Research Design Role Siblings Source Stem cell transplant Stress T-Lymphocyte Testing Therapeutic Thinking Time Transfusion Translating Transplant Recipients Transplantation Tumor Antigens Tumor-Derived Virus Virus Diseases Work base cancer cell cancer immunotherapy cancer therapy cell transformation clinical application clinically relevant conditioning design exhaust frontier graft vs host disease immune function immunosuppressed in vivo innovation killings mortality neoplastic cell novel novel strategies offspring peripheral blood preclinical study prevent public health relevance response theories tumor

项目摘要

DESCRIPTION (provided by applicant): Gamma Delta-T cells are a rare subpopulation of T lymphocytes with unique antitumor and antiviral properties making them ideal to study in the context of developing novel approaches to treat malignant or infectious diseases. Recent advances by ourselves and others have led to the development of the scientific rationale and the technical means necessary to perform early-phase human clinical trials designed to exploit the innate antitumor properties of Gamma Delta T-cells. Two general approaches are currently being taken in this regard, both relying upon either the in vivo activation or the ex vivo expansion (and subsequent re-infusion) of autologous (i.e., patient-derived) Gamma Delta-T cells. However, central to this proposal's rationale, new findings have now established that when compared to Gamma Delta-T cells found in healthy donors, Gamma Delta-T cells found in tumor-bearing hosts appear to be substantially diminished in number, or are functionally impaired in a variety of important ways. Objectives: We hypothesize that in the majority of tumor-bearing hosts, the Gamma Delta-T cell compartment is irreversibly "damaged" or "exhausted", this possibly occurring in a tumor-dependent manner. Accordingly, we propose that the use of patient-derived (i.e., autologous) Gamma Delta-T cells for cancer immunotherapy may be undesirable or even impossible. Given this, here we introduce the highly novel concept of using adoptively transferred allogeneic Gamma Delta-T cells for the treatment of cancer or viral infections. In putting forth this highly novel concept, we cite both biological and clinical reasons why the introduction of allogeneic (donor-derived) Gamma Delta-T cells might best be undertaken in the setting of an allogeneic hematopoietic stem cell (HSC) transplant. Thus, contrary to convention, here we propose a highly iconoclastic model in which allogeneic HSC transplantation will not be used as a therapy in itself, but rather as a "therapeutic platform" for the subsequent delivery of therapeutic donor-derived Gamma Delta-T cells. Three aims are proposed. Aim 1 (Proof-of-concept studies): To determine the extent to which donor-derived Gamma Delta-T cells (administered following a fully ablative allogeneic HSC transplant) can eradicate disease in selected mouse tumor models. These studies will be used to establish for the first time, the concept and convention of the "Gamma Delta-T cell donor lymphocyte infusion", heretofore referred to as "Gamma Delta-T cell DLI". Aim 2 (Pre-clinical studies to more closely approximate human clinical applications): To determine the extent to which Gamma Delta-T cell DLI (administered following a nonmyeloablative allogeneic HSC transplant) can eradicate tumors in mice. These studies will be used to extend the concept of the "Gamma Delta-T cell DLI" into a model which is the most likely to be rapidly adapted for clinical use. Aim 3 (Pre-clinical studies to test a second entirely new approach to allogeneic Gamma Delta-T cell-based therapy): To determine the extent to which transient lymphodepletion of tumor-bearing hosts permits the temporary transfer of tumor-reactive allogeneic Gamma Delta-T cells. These never-before proposed models represent a new paradigm for the treatment of cancers, selected virus infections, and possibly, cancers arising as a consequence of infection with oncogenic viruses.

描述（由申请人提供）：Gamma Delta-T 细胞是一种罕见的 T 淋巴细胞亚群，具有独特的抗肿瘤和抗病毒特性，使其成为开发治疗恶性或传染病的新方法的理想选择。我们和其他人的最新进展导致了进行旨在利用 Gamma Delta T 细胞先天抗肿瘤特性的早期人体临床试验所需的科学原理和技术手段的发展。目前在这方面正在采取两种通用方法，均依赖于自体（即源自患者的）Gamma Delta-T 细胞的体内激活或离体扩增（以及随后的再输注）。然而，该提案基本原理的核心是，现在的新发现表明，与健康捐赠者中发现的 Gamma Delta-T 细胞相比，荷瘤宿主中发现的 Gamma Delta-T 细胞数量似乎大幅减少，或者功能受损以各种重要的方式。目的：我们假设在大多数荷瘤宿主中，Gamma Delta-T 细胞区室受到不可逆的“损坏”或“耗尽”，这可能以肿瘤依赖性方式发生。因此，我们建议使用患者来源的（即自体）Gamma Delta-T 细胞进行癌症免疫治疗可能是不可取的，甚至是不可能的。鉴于此，我们在这里介绍使用过继转移的同种异体 Gamma Delta-T 细胞来治疗癌症或病毒感染的高度新颖的概念。在提出这个高度新颖的概念时，我们引用了生物学和临床原因，说明为什么最好在同种异体造血干细胞 (HSC) 移植的情况下引入同种异体（供体来源的）Gamma Delta-T 细胞。因此，与惯例相反，我们在这里提出了一种高度反传统的模型，其中同种异体 HSC 移植本身不会用作治疗，而是作为随后递送治疗性供体来源的 Gamma Delta-T 细胞的“治疗平台” 。提出了三个目标。目标 1（概念验证研究）：确定供体来源的 Gamma Delta-T 细胞（在完全消融同种异体 HSC 移植后施用）可以在选定的小鼠肿瘤模型中根除疾病的程度。这些研究将首次用于建立“Gamma Delta-T 细胞供体淋巴细胞输注”的概念和惯例，此前称为“Gamma Delta-T 细胞 DLI”。目标 2（更接近人类临床应用的临床前研究）：确定 Gamma Delta-T 细胞 DLI（在非清髓性同种异体 HSC 移植后施用）可以根除小鼠肿瘤的程度。这些研究将用于将“Gamma Delta-T 细胞 DLI”的概念扩展为最有可能快速适应临床使用的模型。目标 3（临床前研究，测试第二种全新的同种异体 Gamma Delta-T 细胞治疗方法）：确定荷瘤宿主的短暂淋巴清除在多大程度上允许肿瘤反应性同种异体 Gamma Delta 暂时转移-T细胞。这些前所未有的模型代表了治疗癌症、特定病毒感染以及可能因致癌病毒感染而产生的癌症的新范例。