Phase I/II Randomized Tiral of Adoptive Lymphocyte Transfer in Ovarian Cancer

描述(由申请人提供)： 卵巢癌是一种孤儿疾病，也是妇科癌症最常见的死亡原因。尽管取得了多种化疗进展，但卵巢癌的死亡率在过去20年里没有变化，因此迫切需要开发有效的替代治疗策略。研究人员现在已经找到了卵巢癌患者自然抗肿瘤免疫反应的重要证据。这包括发现肿瘤内T细胞积聚与无进展和总存活率相关；肿瘤内和循环中T细胞具有肿瘤特异性的证据；以及肿瘤微环境中特定细胞和可溶性免疫抑制因素的阐明。随着克服关键免疫抑制障碍的新技术和方法的出现，现在第一次有机会为卵巢癌开发强大的免疫疗法。 在免疫疗法中，过继转移自然发生的或疫苗诱导的肿瘤反应性T细胞已成为迄今为止治疗晚期恶性肿瘤患者最有前途的方法。最近的突破培养了人们的乐观情绪，即过继免疫疗法的承诺现在可以大规模实现。首先，在T细胞转移之前去除宿主淋巴可以增强被转移细胞的抗肿瘤效果。其次，开发向T细胞传递共刺激信号的人工平台可以显著延长体内转移的淋巴细胞的存活时间和功能。第三，细胞输注后强有力的癌症疫苗是有益的，而且通常对于根除体内已建立的肿瘤是必要的。在这种能力下，树突状细胞是有吸引力的细胞疫苗，因为它们可以负载自体肿瘤裂解物，呈现出广泛的肿瘤相关抗原。最后，调节性T细胞被证明可以抑制宿主的抗肿瘤活性，开发药物干预来减弱它们，如节律环磷酰胺化疗，可能会增强肿瘤免疫，尽管它对效应器T细胞的影响尚不清楚。 由于癌症疫苗已显示出实质性的前景，但疗效有限，研究人员的基本假设是，过继转移自体体外CD3/CD28共刺激疫苗诱导的T细胞在 淋巴去除、强有力的癌症疫苗接种和口服节律环磷酰胺将增强宿主抗肿瘤免疫，使其达到优于单独接种疫苗的水平，并诱导难治性卵巢癌患者的肿瘤消退。研究人员提出了一项1/2期随机临床研究，即维持疫苗联合口服节律环磷酰胺，在过继转移疫苗启动的CD3/CD8共刺激的自体T细胞的情况下，治疗既往接种过DCVAX-L的患者的复发卵巢癌。DCVAX-DCVAX是一种负载自体肿瘤细胞裂解物的树突状细胞疫苗。

DESCRIPTION (provided by applicant): Ovarian cancer is an orphan disease and the most common cause of death from gynecologic cancers. Despite multiple chemotherapeutic advances, the death rate from ovarian cancer has not changed over the past two decades creating a strong need to develop potent alternative treatment strategies. The investigators have now developed significant evidence of natural anti-tumor immune responses in patients with ovarian cancer. This includes the finding that intratumoral T cell accumulation correlates with progression-free and overall survival; evidence of intratumoral and circulating T cells with tumor-specificity; and the elucidation of specific cellular and soluble immunosuppressive elements in the tumor microenvironment. With the advent of novel technology and approaches to overcome key immunosuppressive barriers, the opportunity now exists for the first time to develop powerful immunotherapies for ovarian cancer. Among immune therapies, adoptive transfer of naturally occurring or vaccine-induced tumor-reactive T cells has emerged as the most promising approach to date for the treatment of patients with advanced malignancies. Recent breakthroughs have fostered optimism that the promise of adoptive immunotherapy can now be materialized at a large scale. First, host lymphodepletion prior to T cell transfer can augment the anti- tumor efficacy of the transferred cells. Second, the development of artificial platforms to deliver costimulation to T cells can significantly extend survival and function of transferred lymphocytes in vivo. Third, a robust cancer vaccine boost following cell infusion is beneficial and often necessary to eradicate established tumors in vivo. In this capacity, dendritic cells are attractive cellular vaccines as they can be loaded with autologous tumor lysate to present a broad repertoire of tumor-associated antigens. Lastly, regulatory T cells have been shown to suppress host anti-tumor activity and the development of pharmacologic interventions to attenuate them, such as metronomic cyclophosphamide chemotherapy, may potentiate tumor immunity, although its impact on effector T cells is unknown. Since cancer vaccination has shown substantial promise but limited efficacy, it is the investigators fundamental hypothesis that a combination of adoptive transfer of autologous ex vivo CD3/CD28 costimulated vaccine-induced T cells after lymphodepletion, robust cancer vaccination, and oral metronomic cyclophosphamide will potentiate host anti-tumor immunity to levels superior to vaccine alone, and induce tumor regression in patients with refractory ovarian cancer. The investigators propose a Phase 1/2 randomized clinical study of maintenance vaccination combined with oral metronomic cyclophosphamide with or without adoptive transfer of vaccine-primed CD3/CD8-costimulated autologous T cells for recurrent ovarian cancer in patients previously vaccinated with DCVax-L, an autologous tumor cell lysate-loaded dendritic cell vaccine.