Abstract
OBJECTIVE: We initiated studies to develop cytokine-secreting human ovarian carcinoma cells for the purpose of using these cells as vaccines for the treatment of advanced epithelial ovarian cancer. STUDY DESIGN: A human ovarian carcinoma cell line (UCI-107) was genetically engineered to secrete the cytokine interleukin-2 by retroviral-mediated gene transduction. RESULTS: One clone, termed UCI-107A IL-2 AS, constitutively secreted high levels of interleukin-2 (i.e., 2000 to 2300 pg/ml/10 5 cells per 48 hours) for >55 passages and 8 months of study. Unlike parental- and vector-transduced cells, UCI-107A IL-2 AS cells were aneuploid and failed to express major histocompatibility complex class I and HER2/ neu surface antigens. UCI-107A IL-2 AS cells were highly resistant to killing by gamma irradiation and continued to produce high levels of interleukin-2 even after irradiation with 10,000 cGy. Balb/C nude mice injected intraperitoneally with UCI-107A IL-2 AS cells survived significantly longer than control animals, with 25% of the animals totally rejecting their tumors. UCI-107A IL-2 AS was totally resistant to killing by fresh allogeneic peripheral blood lymphocytes in four hour chromium 51 release assays but induced high levels of killing in 72-hour long-term cytotoxic assays. CONCLUSION: The potential use of these interleukin-2 - secreting ovarian carcinoma cells as vaccines for women with advanced ovarian cancer will be discussed. (AM J OBSTET GYNECOL 1996;174:633-40.)
Highlights
Title Development and characterization of an interleukin-2-transduced human ovarian carcinoma tumor vaccine not expressing major histocompatibility complex molecules
Dusty Miller (Fred Hutchinson Cancer Center, Seattle, Wash.). This plasmid, derived from a Maloney murine leukemia virus, contains the neophosphotransferase gene whose constitutive expression is driven by the SV40 enhancer-promoter, and the 5' retroviral long terminal repeat of the integrated vector drives the expression of an inserted gene. 14The human IL-2 complementary deoxyribonucleic acid (DNA) was obtained from American Type Culture Collection (Rockville, Md.) in the Okaiama and Berg pCD cloning vector and was excised with BamHI restriction enzyme
The antitumor potential of peripheral blood lymphoid cells from healthy donors was assessed with a previously described 72-hour long-term cytotoxicity assay that uses a crystal violet dye method.!" The degree of tumor cell destruction mediated by peripheral blood lymphoid cell (PBL) was quantified by the following formula: Absorbance of tumor cells treated with PBL x 100
Summary
We initiated studies to develop cytokine-secreting human ovarian carcinoma cells for the purpose of using these cells as vaccines for the treatment of advanced epithelial ovarian cancer. The number of potential tumor antigens can include any amino acid sequence carrying a single point mutation in any cellular protein, either membrane bound or intracellular These peptides, specific to the tumor cell, may be used as target antigens for recognition and activation of specific cytotoxic T cells.[4] Recent results indicate that even spontaneous and poorly immunogeneic murine tumors can be recognized by antigen-specific effector cells if the tumor cells are genetically altered to secrete cytok i n e s 9 Henceit is possible that the immune system fails. We have generated and characterized a human ovarian carcinoma cell line genetically engineered to secrete high levels of IL-2 by retroviral-mediated gene transduction. The potential use of these cells as a vaccine for women with advanced ovarian cancer will be discussed
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