Gamma Delta T Cell Immunotherapy of Breast Cancer

乳腺癌的 Gamma Delta T 细胞免疫治疗

基本信息

批准号：
7290717
负责人：
RICHARD D LOPEZ
金额：
$ 30.54万
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：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7290717
关键词：
Address Adjuvant Adoptive Immunotherapy Adriamycin PFS Adverse effects Affect Age Animal Model Antigens Apoptosis Appendix Autoantigens Autologous Biodistribution Biological Biology Blood Blood Cells Blood Circulation Blood Volume Blood typing procedure Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Cancer Patient Cancer cell line Cancerous Categories Cell Count Cells Clinical Clinical Data Clinical Research Clinical Treatment Clinical Trials Clinical Trials Design Cytolysis Data Defect Development Disease Dose Epithelial Fatty acid glycerol esters Foundations Funding Future Generations Goals Grant Growth Human Immune response Immune system Immunologic Monitoring Immunotherapy In Vitro Individual Infusion procedures Interleukin-12 Interleukin-15 Investigational Drugs Investigational New Drug Application Kinetics Laboratories Major Histocompatibility Complex Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Mammary gland Methodology Methods Microscopic Mind Mitogens Modeling Mus Newly Diagnosed Nude Mice Numbers Palpable Patients Peptides Pharmaceutical Preparations Phase I Clinical Trials Phase II Clinical Trials Play Population Pre-Clinical Model Principal Investigator Prior Chemotherapy Prior Therapy Process Production Property Publishing Range Refractory Relapse Relative (related person)Reporting Research Design Research Personnel Resistance Role Schedule Signal Pathway Staging Standards of Weights and Measures Stress T-Cell Receptor T-Lymphocyte Testing Tissues Toxic effect Treatment Protocols Tumor Antigens Tumor Cell Line Tumor Specific Peptide United States Food and Drug Administration Week Woman Work antigen processing base bisphosphonate cancer cell cancer therapy cancer type cell killing cell transformation chemotherapy clinical effect cytotoxicity design in vivo indexing intravenous administration killings malignant breast neoplasm melanoma method development neoplastic cell novel novel strategies peripheral blood pre-clinical programs scale up therapy resistant tumor volunteer

项目摘要

yS-T cells are a rare subpopulation of T lymphocytes with unique antitumor properties. Cancerous cells - particularly those of epithelial origin - are nowknown to display a variety of stress-induced antigens (such as MICA/B), which can serve as recognition determinants for the human y8-T cell receptor (TCR) and associated accessory molecules. Thus, in order to kill tumor cells, y8-T cells do not require the presence of tumor-specific antigens, tumor antigen processing or major histocompatibility complex (MHC) display of tumor-specific peptides. Given this, we propose that y8-T cells are ideal to study in the context of developing novel approaches for the primary or adjuvant treatment of a number of common human cancers of epithelial origin - including breast cancer. Nevertheless, despite the theoretical promise of y8-T cell-based immunotherapy, to date clinical studies to examine this question are only now in the earliest stages of development. Indeed, until very recently, no practical means existed to generate the large numbers of y8-T cells required for clinical-scale administration. Rationale: We initially identified a CD2-initiated signaling pathway which inhibits apoptosis in mitogen-stimulated human y8-T cells. By exploiting this signaling pathway, our laboratory has pioneered the development of the methods permitting the large-scale ex vivo expansion of human y8-T cells. Importantly, these y8-T cells retain potent innate antitumor activity in vitro against a variety of human tumor cell lines, including breast cancer cell lines. In addition, our preliminary studies demonstrate that when administered intravenously, these y5-T cells can inhibit the growth of human breast cancer tumors established in nude mice. Together, these findings provide both the biological and clinical rationale for the studies proposed in this grant. Approach: The aims of this proposal are as follows. Aim 1: To characterize the y8-T cell population present in breast cancer patients in regard to numbers in the circulation, their ability to be expanded ex vivo and their cytotoxicity to breast cancer cells. Aim 2: To optimize and standardize the large-scale expansion and purification of human y5-T cells for subsequent use in clinical trials. Studies from this aim will yield an IND application to be filed with the US FDA. Aim 3: To examine and optimize expanded human yS-T cell immunotherapy in a human xenogeneic breast cancer model. Aim 4: To initiate clinical trials of y8-T cell immunotherapy in patients with therapy-resistant metastatic breast cancer. Long-term objectives: We propose to follow our first-generation trial with subsequent Phase I studies that will combine the y5-T cell regimen with immunomodulatoryagents and/or chemotherapy based on observations made in our animal models. These studies would then form the basis for future Phase II trials incorporating such treatment strategies. Lay description: y8-T cells are a rare type of blood cell which can naturally kill cancer cells making them ideal to study as a new form of cancer therapy. However, they are extremely difficult to grow in the laboratory. As we have discovered a means to generate large numbers of these cells, we are now able to propose clinical studies designed to examine how these rare tumor-killing cells might be used as a newform of treatment for breast cancer - or other types of cancers.

yS-T 细胞是一种罕见的 T 淋巴细胞亚群，具有独特的抗肿瘤特性。癌细胞—— 特别是那些上皮来源的抗原 - 现在已知可以展示多种应激诱导的抗原（例如 MICA/B)，可作为人类 y8-T 细胞受体 (TCR) 的识别决定簇相关的辅助分子。因此，为了杀死肿瘤细胞，y8-T细胞不需要存在肿瘤特异性抗原、肿瘤抗原加工或主要组织相容性复合物 (MHC) 展示肿瘤特异性肽。鉴于此，我们建议 y8-T 细胞是在发育中研究的理想选择用于主要或辅助治疗多种常见人类上皮癌的新方法起源 - 包括乳腺癌。然而，尽管基于 y8-T 细胞的理论上有希望免疫疗法，迄今为止检验这个问题的临床研究现在才处于最早阶段发展。事实上，直到最近，还没有实际的方法来生成大量 y8-T 临床规模管理所需的细胞。理由：我们最初鉴定了 CD2 启动的信号传导抑制丝裂原刺激的人 y8-T 细胞凋亡的途径。通过利用这个信号途径，我们的实验室率先开发了允许大规模离体人类 y8-T 细胞的扩增。重要的是，这些 y8-T 细胞在体外保留了有效的先天抗肿瘤活性对抗多种人类肿瘤细胞系，包括乳腺癌细胞系。此外，我们初步研究表明，当静脉注射时，这些 y5-T 细胞可以抑制人类细胞的生长。在裸鼠中建立乳腺癌肿瘤。总之，这些发现提供了生物学和本次资助中提出的研究的临床原理。方法：本提案的目标如下。目标 1：根据细胞中的数量来表征乳腺癌患者中存在的 y8-T 细胞群循环、离体扩增的能力及其对乳腺癌细胞的细胞毒性。目标 2：优化和标准化人y5-T细胞的大规模扩增和纯化以供后续使用在临床试验中。针对这一目标的研究将产生向美国 FDA 提交的 IND 申请。目标 3：检查并优化人类异种乳腺癌中的扩展人类 yS-T 细胞免疫疗法模型。目标 4：在耐药转移患者中启动 y8-T 细胞免疫疗法的临床试验乳腺癌。长期目标：我们建议在第一代试验之后进行后续阶段我的研究将 y5-T 细胞疗法与免疫调节剂和/或化疗相结合根据我们在动物模型中所做的观察。这些研究将构成未来第二阶段的基础纳入此类治疗策略的试验。简单描述：y8-T 细胞是一种罕见的血细胞，可以自然地杀死癌细胞，使其成为研究新型癌症疗法的理想选择。然而，他们是在实验室中生长极其困难。正如我们发现了一种产生大量这些细胞，我们现在能够提出临床研究，旨在检查这些罕见的肿瘤杀伤作用细胞可能被用作乳腺癌或其他类型癌症的新治疗方法。