Resistance to apoptosis in clinical melanoma gene therapy

描述(由申请人提供)：加州大学洛杉矶分校/加州理工大学工程免疫项目正在进行一系列使用F5 Mart T细胞受体(TCR)工程T细胞进行过继细胞治疗的临床研究。表达这种高亲和力TCR的T淋巴细胞对HLAA*0201/MART阳性黑色素瘤靶点具有高度的细胞毒作用，释放I型细胞因子，给患者使用时具有非常高的生物学活性。在最近完成的一项试验中，对8名患有转移性黑色素瘤的条件患者进行了109 F5 Mart CTL治疗，其中6名患者显示出肺、肝、骨、淋巴和皮肤等可测量疾病部位肿瘤显著消退的证据。然而，所有这些都在三个月内复发。我们的目标是研究来自这些患者的早期传代患者来源的黑色素瘤细胞系对F5Mart CTL诱导的细胞毒性的敏感性或耐药性的机制。我们假设，表观遗传控制的信号通路的非调控激活以及促和抗凋亡基因产物比例的不平衡有利于免疫耐受表型。此外，获得性和/或固有的抗性可以被染色质重塑分子如HDACi(SAHA)逆转。成功实施所提出的特定目标将识别表观遗传调控的信号转导途径(S)和与黑色素瘤对F5 Mart CTL耐药有关的凋亡相关基因产物。这最终导致了小分子抑制剂(增敏剂)的使用，这些小分子抑制剂可以特异性地靶向解除调控的信号通路的组成部分，并通过调节与凋亡相关的基因产物的表达谱，有利于促进凋亡的环境，从而赋予敏感的表型。 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他们自己的白血球，这些白血球经过基因工程，可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，并有可能确定使这种癌症治疗更有效的改进措施。

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.