Immunotherapy for peritoneal ovarian carcinoma metastasis using ex vivo expanded tumor infiltrating lymphocytes

Surgery and chemotherapy have contributed to a modest overall survival in patients with epithelial ovarian carcinoma. It is therefore important to pursue novel therapy strategies for this disease that are different from conventional chemotherapy. Tumor infiltrating lymphocytes (TILs) from patients with ovarian carcinoma may represent an active immune response of the host directed against the tumor cells. These TILs can be expanded in vitro in low concentrations of recombinant interleukin-2 (rIL-2) by a few thousandfold. The resulting T-cell lines comprise CD3+CD4+TCR alpha beta + or CD3+CD8+TCR alpha beta + cells, or mixtures of both. These T-cell lines may exhibit either tumor-specific cytotoxicity against autologous tumor cells, or produce cytokines (interferon-gamma, tumor necrosis factor, and granulocyte stimulating factor) either in antigen-dependent (tumor-specific) or an antigen-independent manner. T-cell lines exhibiting primarily autologous tumor-specific cytotoxicity were developed from approximately 50% of the patients. Blocking experiments using appropriate monoclonal antibodies revealed that the CD3/TCR complex on the effector cells and the MHC class I antigens on the tumor cells were involved in the cytolytic process. We have developed a four-step method for the expansion of TILs to large numbers (1 x 10(10) to 1 x 10(11)) sufficient for clinical trials in patients with ovarian cancer. We have conducted a pilot clinical trial to examine the feasibility and clinical effects of intraperitoneal TILs and low-dose rIL-2 in patients with advanced ovarian carcinoma who were refractory to platinum-based chemotherapy. More recently, procedures have been developed for obtaining large numbers of purified CD8+ rIL-2-expanded TILs for the treatment of patients with ovarian carcinoma. The evolution of clinical trials and correlative studies necessary to develop an effective adoptive immunotherapy approach were discussed.