Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer

doi:10.1084/jem.173.5.1047

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Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer

T Blankenstein, ZH Qin, K Uberla, W Muller, H Rosen, HD Volk and T Diamantstein
Institut fur Immunologie, Universitatsklinikum Steglitz, Freie Universitat Berlin, FRG.

The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF- alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor- infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF- alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.
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Galanis, E., Hersh, E. M., Stopeck, A. T., Gonzalez, R., Burch, P., Spier, C., Akporiaye, E. T., Rinehart, J. J., Edmonson, J., Sobol, R. E., Forscher, C., Sondak, V. K., Lewis, B. D., Unger, E. C., O'Driscoll, M., Selk, L., Rubin, J. (1999). Immunotherapy of Advanced Malignancy by Direct Gene Transfer of an Interleukin-2 DNA/DMRIE/DOPE Lipid Complex: Phase I/II Experience. JCO 17: 3313-3323 [Abstract] [Full Text]
Fujii, S.-i., Hamada, H., Fujimoto, K., Shimomura, T., Kawakita, M. (1999). Activated Dendritic Cells From Bone Marrow Cells of Mice Receiving Cytokine-Expressing Tumor Cells Are Associated With the Enhanced Survival of Mice Bearing Syngeneic Tumors. Blood 93: 4328-4335 [Abstract] [Full Text]
de Zoeten, E., Carr-Brendel, V., Markovic, D., Taylor-Papadimitriou, J., Cohen, E. P. (1999). Treatment of Breast Cancer with Fibroblasts Transfected with DNA from Breast Cancer Cells. J. Immunol. 162: 6934-6941 [Abstract] [Full Text]
Greten, T. F., Jaffee, E. M. (1999). Cancer Vaccines. JCO 17: 1047-1047 [Abstract] [Full Text]
Zhai, Y., Ni, J., Jiang, G.-w., Lu, J., Xing, L., Lincoln, C., Carter, K. C., Janat, F., Kozak, D., Xu, S., Rojas, L., Aggarwal, B. B., Ruben, S., Li, L.-y., Gentz, R., Yu, G.-l. (1999). VEGI, a novel cytokine of the tumor necrosis factor family, is an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vivo. FASEB J. 13: 181-189 [Abstract] [Full Text]
Bowman, L., Grossmann, M., Rill, D., Brown, M., Zhong, W.-y., Alexander, B., Leimig, T., Coustan-Smith, E., Campana, D., Jenkins, J., Woods, D., Kitchingman, G., Vanin, E., Brenner, M. (1998). IL-2 Adenovector-Transduced Autologous Tumor Cells Induce Antitumor Immune Responses in Patients With Neuroblastoma. Blood 92: 1941-1949 [Abstract] [Full Text]
Petersson, M., Charo, J., Salazar-Onfray, F., Noffz, G., Mohaupt, M., Qin, Z., Klein, G., Blankenstein, T., Kiessling, R. (1998). Constitutive IL-10 Production Accounts for the High NK Sensitivity, Low MHC Class I Expression, and Poor Transporter Associated with Antigen Processing (TAP)-1/2 Function in the Prototype NK Target YAC-1. J. Immunol. 161: 2099-2105 [Abstract] [Full Text]
de Zoeten, E. F., Carr-Brendel, V., Cohen, E. P. (1998). Resistance to Melanoma in Mice Immunized with Semiallogeneic Fibroblasts Transfected with DNA from Mouse Melanoma Cells. J. Immunol. 160: 2915-2922 [Abstract] [Full Text]
Osanto, S. (1997). Vaccine Trials for the Clinician: Prospects for Tumor Antigens. The Oncologist 2: 284-299 [Abstract] [Full Text]
Maria, B. L., Medina, C. D., Hoang, K. B.N., Phillips, M. I. (1997). Topical Review: Gene Therapy for Neurologic Disease: Benchtop Discoveries to Bedside Applications. 1. The Bench. J Child Neurol 12: 1-12 [Abstract]
Guo, Y, Wu, M, Chen, H, Wang, X, Liu, G, Li, G, Ma, J, Sy, M. (1994). Effective tumor vaccine generated by fusion of hepatoma cells with activated B cells. Science 263: 518-520 [Abstract]