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.

Public Health Relevance

Ovarian cancer is classified as an orphan disease, however its prevalence and unwavering death rate mandate the development of novel therapeutic strategies. Our innovative clinical investigations and immunomonitoring studies will answer fundamental questions of clinical immunology, evaluate the anti-tumor potential of the host immune system, and serve as a guide in the rational design of treatment regimens that best support the induction of strong anti-tumor responses in vivo and provide the greatest clinical benefit to patients with refractory ovarian cancer.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (S1))
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Needleman, Katherine
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University of Pennsylvania
Obstetrics & Gynecology
Schools of Medicine
United States
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Zsiros, Emese; Duttagupta, Priyanka; Dangaj, Denarda et al. (2015) The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28-Costimulated T Cells Prepared for Adoptive Therapy. Clin Cancer Res 21:2840-50
Zsiros, Emese; Tanyi, Janos; Balint, Klara et al. (2014) Immunotherapy for ovarian cancer: recent advances and perspectives. Curr Opin Oncol 26:492-500
Kandalaft, Lana E; Chiang, Cheryl L; Tanyi, Janos et al. (2013) A Phase I vaccine trial using dendritic cells pulsed with autologous oxidized lysate for recurrent ovarian cancer. J Transl Med 11:149
Kandalaft, Lana E; Powell Jr, Daniel J; Chiang, Cheryl L et al. (2013) Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. Oncoimmunology 2:e22664