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Cancer Immunotherapy Using Irradiated Tumor Cells Secreting Heat Shock Protein 70

Departments of ¹ Pathology, ² Obstetrics and Gynecology, ³ Molecular Microbiology and Immunology, and ⁴ Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland and ⁵ Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan

Requests for reprints: Chien-Fu Hung, Departments of Pathology and Oncology, The Johns Hopkins University School of Medicine, CRB II Room 307, 1550 Orleans Street, Baltimore, MD 21231. Phone: 410-614-3899; Fax: 443-287-4295; E-mail: chung2{at}jhmi.edu.

Ovarian cancer is responsible for the highest mortality rate among patients with gynecologic malignancies. Therefore, there is an emerging need for innovative therapies for the control of advanced ovarian cancer. Immunotherapy has emerged as a potentially plausible approach for the control of ovarian cancer. In the current study, we have generated heat shock protein 70 (Hsp70)-secreting murine ovarian cancer cells that express luciferase (MOSEC/luc). Hsp70 has been shown to target and concentrate antigenic peptides in dendritic cells and is also able to activate dendritic cells. We characterized the antigen-specific immune response and the antitumor effect of the MOSEC/luc cells expressing Hsp70 using noninvasive luminescence images to measure the amount of ovarian tumors in the peritoneal cavity of mice. We found that mice challenged with MOSEC/luc cells expressing Hsp70 generate significant antigen-specific CD8⁺ T-cell immune responses. Furthermore, we also found that mice vaccinated with irradiated MOSEC/luc cells expressing Hsp70 generate significant therapeutic effect against MOSEC/luc cells. In addition, we have shown that CD8⁺, natural killer, and CD4⁺ cells are important for protective antitumor effect generated by irradiated tumor cell–based vaccines expressing Hsp70. Moreover, we also found that CD40 receptor is most important, followed by Toll-like receptor 4 receptor, for inhibiting in vivo tumor growth of the viable MOSEC/luc expressing Hsp70. Thus, the use of Hsp70-secreting ovarian tumor cells represents a potentially effective therapy for the control of lethal ovarian cancer. [Cancer Res 2007;67(20):10047–57]