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

描述（由申请人提供）： 卵巢癌是一种罕见疾病，也是妇科癌症最常见的死亡原因。 尽管有多种化疗进展，但卵巢癌的死亡率在过去二十年中没有改变，因此迫切需要开发有效的替代治疗策略。 研究人员现在已经发现了卵巢癌患者天然抗肿瘤免疫反应的重要证据。这包括肿瘤内T细胞积聚与无进展生存期和总生存期相关的发现;肿瘤内和循环T细胞具有肿瘤特异性的证据;以及肿瘤微环境中特异性细胞和可溶性免疫抑制成分的阐明。 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，天然存在的或疫苗诱导的肿瘤反应性T细胞的过继转移已成为迄今为止治疗晚期恶性肿瘤患者的最有希望的方法。 最近的突破使人们乐观地认为，过继免疫疗法的前景现在可以大规模实现。 首先，在T细胞转移之前的宿主淋巴细胞清除可以增强转移的细胞的抗肿瘤功效。 第二，开发人工平台以向T细胞递送共刺激可以显著延长体内转移的淋巴细胞的存活和功能。 第三，细胞输注后的强有力的癌症疫苗加强是有益的，并且通常是根除体内已建立的肿瘤所必需的。 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以呈递广泛的肿瘤相关抗原库。最后，调节性T细胞已被证明可以抑制宿主的抗肿瘤活性，而减弱它们的药理学干预措施的发展，如节拍环磷酰胺化疗，可能会增强肿瘤免疫力，尽管其对效应T细胞的影响尚不清楚。 由于癌症疫苗接种已显示出实质性的希望但效力有限，因此研究者的基本假设是，自体离体CD 3/CD 28共刺激疫苗诱导的T细胞的过继转移的组合在肿瘤发生后， 淋巴细胞清除、强力癌症疫苗接种和口服节拍环磷酰胺将增强宿主抗肿瘤免疫力至上级单独疫苗的水平，并诱导患有难治性卵巢癌的患者的肿瘤消退。 研究人员提出了一项1/2期随机临床研究，在既往接种过DCVax-L（一种自体肿瘤细胞裂解物负载的树突状细胞疫苗）的患者中，维持疫苗接种联合口服节拍式环磷酰胺，伴或不伴疫苗引发的CD 3/CD 8共刺激自体T细胞过继转移，用于复发性卵巢癌。

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.