Resistance to apoptosis in clinical melanoma gene therapy

临床黑色素瘤基因治疗中的细胞凋亡抵抗

• 批准号: 8110335
• 负责人: Ali Jazirehi
• 金额: $ 28.09万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110335
• 关键词: Adoptive Immunotherapy; Affinity; Antigen Presentation; Antigen Targeting; Antigens; Apoptosis; Apoptotic; Archives; Baltimore; Biopsy; Cell Line; Cell Therapy; Cells; Clinical; Clinical Trials; Cutaneous; Dendritic Cell Vaccine; Disease; Disorder by Site; Dose; Engineering; Enrollment; Epigenetic Process; Figs - dietary; Grant; HLA-A2.1; Histone Deacetylase Inhibitor; Immune; Immunity; In Vitro; Interleukin-2; Leukapheresis; Leukocytes; Liver; Lung; Lymphocyte; MART-1 Tumor Antigen; Measurable Disease; Melanoma Cell; Metastatic Melanoma; Metastatic Skin Cancer; Modification; Molecular Profiling; Pathway interactions; Patients; Peptides; Phenotype; Physiologic pulse; Proteins; Protocols documentation; Regimen; Relapse; Research; Research Personnel; Resistance; Resources; Series; Signal Pathway; Signal Transduction Pathway; Skin; T-Cell Receptor; T-Lymphocyte; Therapeutic Intervention; Transgenic Organisms; Vaccines; Variant; Vorinostat; Yang; Zolinza; bone; cancer cell; cancer therapy; chemotherapy; chromatin remodeling; conditioning; cytokine; cytotoxic; cytotoxicity; gene therapy; inhibitor/antagonist; killings; lymph nodes; melanoma; neoplastic cell; programs; small molecule; tumor; vector

DESCRIPTION (provided by applicant): The UCLA/Caltech Program in Engineered Immunity is conducting a series of adoptive cell therapy clinical investigations using F5 MART T cell receptor (TCR) engineered T cells. T lymphocytes engineered to express this high affinity TCR are highly cytotoxic towards HLA A*0201/ MART-positive melanoma targets, release type I cytokines and are biologically very active when administered to patients. In a recently completed trial in which 109 F5 MART CTL were administered to 8 conditioned patients with metastatic melanoma, 6 showed evidence of dramatic tumor regression in measurable disease sites such as lung, liver, bone, lymph node and skin. All however, relapsed within three months. Our objective is to study the mechanism of sensitivity or resistance of early passage patient-derived melanoma cell lines from these patients, and from two successor trials, to F5 MART CTL-induced cytotoxicity. We hypothesize that epigenetically controlled deregulated activation of signaling pathways and an imbalance in the ratio of pro- and anti-apoptotic gene products favor an immune-resistant phenotype. Further, the acquired and/or inherent resistance can be reversed by chromatin remodeling molecules such as HDACi (SAHA). Successful execution of the proposed specific aims will identify epigenetically regulated signal transduction pathway(s) and apoptosis-associated gene products responsible for melanoma resistance to F5 MART CTL. This culminates in the utilization of small molecule inhibitors (sensitizing agents) that can specifically target the components of deregulated signaling pathways and by modulating the expression profile of apoptosis-related gene products favor a pro-apoptotic milieu, thus, conferring a sensitive phenotype. PUBLIC HEALTH RELEVANCE: This grant will support the conduct of a comprehensive analysis of tumor cells derived from patients with metastatic skin cancer (melanoma) after receiving billions of their own white blood cells genetically engineered to recognize and kill their own melanoma cells. These scientific aims will help us better understand why some patients' melanoma cancer cells can be killed, and others not, and to potentially identify improvements to make this kind of cancer treatment more effective.

描述（由申请人提供）：UCLA/Caltech工程免疫项目正在使用F5 MART T细胞受体（TCR）工程T细胞进行一系列过继细胞治疗临床研究。经工程改造以表达这种高亲和力TCR的T淋巴细胞对HLA A*0201/MART阳性黑素瘤靶标具有高度细胞毒性，释放I型细胞因子，并且当施用于患者时具有非常高的生物活性。在最近完成的一项试验中，将109个F5 MART CTL给予8名患有转移性黑色素瘤的条件患者，6名患者显示出在可测量的疾病部位如肺、肝、骨、淋巴结和皮肤中显著的肿瘤消退的证据。然而，所有人都在三个月内复发。我们的目的是研究这些患者的早期传代患者源性黑色素瘤细胞系对F5 MART CTL诱导的细胞毒性的敏感性或抗性机制，以及两项后续试验。我们假设，表观遗传控制的信号通路的激活失调和比例的不平衡的促凋亡和抗凋亡基因产物有利于免疫耐药表型。此外，获得性和/或固有抗性可以通过染色质重塑分子如HDACi（SAHA）逆转。成功执行所提出的特定目标将鉴定表观遗传学调节的信号转导途径和负责黑素瘤对F5 MART CTL的抗性的凋亡相关基因产物。这最终导致利用小分子抑制剂（敏化剂），其可以特异性靶向失调信号传导途径的组分，并通过调节凋亡相关基因产物的表达谱，有利于促凋亡环境，从而赋予敏感表型。 公共卫生相关性：这笔赠款将支持对转移性皮肤癌（黑色素瘤）患者的肿瘤细胞进行全面分析，这些患者接受了数十亿个经过基因工程改造的白色血细胞，以识别和杀死他们自己的黑色素瘤细胞。这些科学目标将帮助我们更好地理解为什么一些患者的黑色素瘤癌细胞可以被杀死，而另一些则不能，并可能确定改进措施，使这种癌症治疗更有效。