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TRANCE- and CD40 Ligand-matured Dendritic Cells Reveal MHC Class I-restricted T Cells Specific for Autologous Tumor in Late-Stage Ovarian Cancer Patients¹

Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania [K. S., P. M. R., A. J. T., B. H., M. V. M., J. L. R., Y. C., B. L. L., R. G. C., C. H. J.], Division of Gynecology and Oncology, Department of Obstetrics and Gynecology [C. S. C., G. C., S. C. R.], and Department of Surgery [E. Y. W., L. R. K.], University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104

Purpose: The use of mature dendritic cells (DCs) presenting tumor-associated antigens (TAAs) to trigger tumor-specific T cells in vivo or in vitro represents a promising approach for cancer immunotherapy. We hypothesized that tumor antigens, mostly unidentified, are present on ovarian tumor cells and that mature DCs could be used to generate tumor-specific responses in unprimed patients. We also sought to measure preexisting antitumor immunity in patients with advanced ovarian cancer.

Experimental Design: Autologous DCs from 10 patients with ovarian cancer were pulsed with killed autologous primary tumors as a source of TAAs. DCs were then cultured in the presence of tumor necrosis factor + TRANCE (tumor necrosis factor-related activation-induced cytokine) to induce maturation. Mature TAA-pulsed DCs were used in vitro to stimulate tumor-specific peripheral blood T cells.

Results: TRANCE and CD40 ligand were effective at maturing DCs. T-cell lines were generated in vitro that were capable of secreting IFN- in response to autologous tumor. These tumor-specific T cells were MHC class I restricted. The frequency of tumor-specific T cells in uncultured cells from malignant ascites fluid and peripheral blood was measured in the same patients.

Conclusions: IFN--secreting tumor-specific T cells were demonstrated at baseline in uncultured T cells from some unvaccinated ovarian cancer patients; however, the T cells could not kill autologous tumor. These data demonstrate that mature DCs presenting tumor antigens from engulfed autologous tumors can be used to augment antitumor immunity in vitro in patients with epithelial ovarian cancer. The results support the feasibility of therapeutic vaccination of ovarian cancer patients.

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				R. Gutzmer, W. Li, S. Sutterwala, M. P. Lemos, J. I. Elizalde, S. L. Urtishak, E. M. Behrens, P. M. Rivers, K. Schlienger, T. M. Laufer, et al. A Tumor-Associated Glycoprotein That Blocks MHC Class II-Dependent Antigen Presentation by Dendritic Cells J. Immunol., July 15, 2004; 173(2): 1023 - 1032. [Abstract] [Full Text] [PDF]