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）：伽马三角细胞是具有独特抗肿瘤和抗病毒特性的T淋巴细胞的罕见亚群，使其非常适合在开发新的治疗恶性或感染性疾病的新方法的情况下进行研究。我们自己和其他人的最新进展导致了科学原理的发展，以及进行早期阶段人类临床试验所必需的技术手段，旨在利用伽玛D-T-Cells的先天抗肿瘤特性。目前在这方面正在采用两种一般方法，既依赖于体内激活或自体（即患者衍生的）伽马D细胞的体内膨胀（以及随后的再灌注）。然而，对于该提案的基本原理的核心，新发现已经确定，与在健康供体中发现的伽马三角细胞相比，在肿瘤宿主中发现的伽马三角-T细胞的数量显着降低，或者在各种重要方面受到功能障碍。目的：我们假设在大多数肿瘤宿主中，伽马三角细胞室是不可逆转地“受损”或“耗尽”的，这可能以肿瘤依赖性的方式出现。因此，我们建议使用患者衍生的（即自体）γ-T细胞进行癌症免疫疗法，甚至是不可能的。鉴于此，在这里，我们介绍了高度新颖的概念，即使用采用的同种异体γ-T Delta-T细胞来治疗癌症或病毒感染。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，这些原因是在同种异体造血干细胞（HSC）移植中，最好最好地引入同种异体（供体）伽马三角-T细胞。因此，与惯例相反，在这里我们提出了一个高度的塑性模型，其中同种异体HSC移植本身不会用作治疗，而是用作随后提供治疗供体供体的伽马delta-T细胞的“治疗平台”。提出了三个目标。 AIM 1（概念验证研究）：确定供体衍生的伽马Delta-T细胞（在完全消融的同种异体HSC移植后施用）可以在选定的小鼠肿瘤模型中消除疾病。这些研究将首次建立，即“伽马Delta-T细胞供体淋巴细胞输注”的概念和惯例（迄今为止）称为“伽马Delta-T细胞DLI”。 AIM 2（临床前研究更紧密地近似人类的临床应用）：确定γ-T Delta-T细胞DLI的程度（在非甲状腺元素同种异体同种异体HSC移植后进行给药）可以消除小鼠的肿瘤。这些研究将用于将“ Gamma Delta-T细胞DLI”的概念扩展到一个模型中，该模型最有可能迅速适应临床使用。 AIM 3（用于测试基于同种异体γ-T细胞细胞的第二个全新方法的临床前研究）：确定肿瘤宿主的短暂淋巴结淋巴结的程度允许临时转移肿瘤反应性同种异体异基因Delta-tta-T细胞。这些从未提出的模型代表了一种用于治疗癌症，选定病毒感染的新范式，甚至可能是由于致癌病毒感染而引起的癌症。