PHASE I STUDY TO EVALUATE THE SAFETY OF CELLULAR ADOPTIVE IMMUNOTHERAPY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。晚期卵巢癌患者通常对手术和化疗有反应，但大多数会因耐药疾病复发。早期复发和残留疾病的治疗为评估基于免疫的疗法的使用提供了一个独特的机会。我们已经开发出从患者外周血中分离抗原特异性T细胞的方法，用于过继免疫治疗的临床试验。以往对黑色素瘤患者的过继免疫治疗试验的一个主要限制是，在缺乏CD4+辅助功能的情况下，注入的CD8+淋巴细胞存活时间较短。CD4+淋巴细胞可能是CD8+生存和功能所必需的，而且可能单独发挥抗肿瘤作用。我们建议在晚期卵巢癌患者中检测过继转移的肿瘤反应性NY-ESO-1特异性CD4+T细胞克隆的安全性和持续时间。第二个目标是评估CD4+T细胞的抗肿瘤效果。研究设计和人群：年龄在18-75岁之间、KPS和GT；=70的III或IV期疾病患者将接受肿瘤表达NY-ESO-1和相关HLA型的筛查。患者将接受白细胞分离，实验室将产生抗原特异性T细胞克隆。如果患者复发或有残留疾病，他们将被提供单一的CD4+T细胞输注。最大耐受剂量将由协议中定义的剂量递增和停止规则确定。为了确定T细胞克隆的持久性，血液样本将通过实时定量聚合酶链式反应进行分析。抗肿瘤反应将通过放射成像和血清CA-125进行评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Patients with advanced ovarian cancer generally respond to surgery and chemotherapy, but most will relapse with chemo-resistant disease. Treatment of early recurrences and residual disease represents a unique opportunity to evaluate the use of immune-based therapies. We have developed methods to isolate antigen-specific T-cells from the peripheral blood of patients for clinical trials of adoptive immunotherapy. A major limitation of previous adoptive immunotherapy trials in melanoma patients was the short survival of infused CD8+ lymphocytes in the absence of CD4+ helper function. CD4+ lymphocytes may be required for CD8+ survival and function, and alone may mediate an anti-tumor effect. We propose to examine the safety and duration of persistence of adoptively transferred tumor-reactive NY-ESO-1-specific CD4+ T-cell clones in patients with advanced ovarian cancer. A secondary objective is to assess the antitumor efficacy of the CD4+ T-cells. Study Design and Population: Patients with Stage III or IV disease between ages 18-75 with a KPS>=70 will be offered screening for tumor expression of NY-ESO-1 and the relevant HLA types. Patients will undergo leukapheresis and antigen specific T cell clones will be generated in the lab. If a patient relapses or has residual disease, they will be offered a single CD4+ T cell infusion. The maximum tolerated dose will be determined by dose escalation and stopping rules defined in the protocol. To determine T cell clone persistence, blood samples will be analyzed by quantitative real-time PCR. Antitumor response will be assessed by radiographic imaging and serum CA-125.