Gamma Delta T Cell Immunotherapy of Breast Cancer

乳腺癌的 Gamma Delta T 细胞免疫治疗

• 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
• 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

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细胞是具有独特抗肿瘤特性的T淋巴细胞的罕见亚群。癌细胞 - 尤其是上皮来源的人 - 现在已知以显示各种应力诱导的抗原（例如 云母/b），可以用作人类Y8-T细胞受体（TCR）的识别决定因素和 相关的附件分子。因此，为了杀死肿瘤细胞，Y8-T细胞不需要 肿瘤特异性抗原，肿瘤抗原加工或主要的组织相容性复合物（MHC）显示 肿瘤特异性肽。鉴于此，我们建议Y8-T细胞在开发的背景下研究 许多普通人类癌的初级或辅助治疗的新方法 起源 - 包括乳腺癌。然而，尽管基于Y8-T基于Y8-T细胞的理论希望 免疫疗法，迄今为止检查这个问题的临床研究仅在现在的最早阶段 发展。确实，直到最近，还没有实用的手段来产生大量的Y8-T 临床规模给药所需的细胞。理由：我们最初确定了CD2引起的信号传导 抑制有丝分裂原刺激的人Y8-T细胞中凋亡的途径。通过利用此信号 途径，我们的实验室率先开发了允许大规模离体的方法的发展 人Y8-T细胞的扩展。重要的是，这些Y8-T细胞在体外保留有效的先天抗肿瘤活性 针对各种人类肿瘤细胞系，包括乳腺癌细胞系。此外，我们的初步 研究表明，当静脉内给药时，这些Y5-T细胞可以抑制人的生长 在裸鼠中建立的乳腺癌肿瘤。这些发现共同提供了生物学和 这项赠款提出的研究的临床原理。方法：该提案的目的如下。 目的1：表征乳腺癌患者中存在的Y8-T细胞群体 循环，将其扩展的体内扩展的能力以及对乳腺癌细胞的细胞毒性。目标2：到 优化和标准化人类Y5-T细胞的大规模扩展和纯化，以供随后使用 在临床试验中。该目标的研究将产生向美国FDA提出的IND应用程序。目标3：到 检查并优化人类异构乳腺癌中的人类T细胞免疫疗法扩大 模型。 AIM 4：启动耐治疗转移性患者Y8-T细胞免疫疗法的临床试验 乳腺癌。长期目标：我们建议遵循我们的第一代试验 I研究将将Y5-T细胞方案与免疫调节剂和/或化学疗法相结合 关于我们动物模型中的观察结果。这些研究将构成未来II期的基础 纳入此类治疗策略的试验。外表描述：Y8-T细胞是一种罕见的血细胞类型 自然可以杀死癌细胞，使其理想地研究为一种新的癌症治疗形式。但是，它们是 在实验室中非常困难。由于我们发现了一种生成大量的方法 这些细胞，我们现在能够提出旨在检查这些罕见肿瘤的临床研究 细胞可以用作乳腺癌或其他类型的癌症治疗的新型。