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

点击翻译按钮获取中文摘要

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.