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Genetic Modification of a Murine Fibrosarcoma to Produce Interleukin 7 Stimulates Host Cell Infiltration and Tumor Immunity¹

Departments of Radiation Oncology [W. H. M., S. C.], Surgery [J. S. E.], Pulmonary and Critical Care Medicine [S. M. D., D. K.], and the Jonsson Comprehensive Cancer Center [W. H. M., J. S. E., S. M. D.], University of California at Los Angeles School of Medicine, Los Angeles, California 90024; Terry Fox Laboratory [J. D. T., D. H., G. J. D.], British Columbia Cancer Research Centre, Vancouver, British Columbia, V5Z1L3, Canada; and Departments of Medical Genetics [J. D. T., D. H.] and Pathology [G. J. D.], University of British Columbia, Vancouver, British Columbia, V6T1W5, Canada

Retroviral-mediated gene transfer was used to introduce and express the gene for murine interleukin 7 (IL-7) in a fibrosarcoma tumor (FSA). The tumorigenicity of these genetically modified FSA cells was greatly decreased in immunologically intact syngeneic mice but was unaltered in T-cell-deprived mice. IL-7-infected tumors that did grow in intact animals from large size inocula did so slowly and had a high incidence of spontaneous regression. Furthermore, mice that had rejected tumors became specifically immune to challenge with uninfected parental tumor cells.

IL-7-infected FSA growing in intact mice were heavily infiltrated with host T-cells that were presumably responsible for slow growth and tumor regression, and tumor cells were in the minority. Fluorescence-activated cell sorter analysis showed that there was a 530% increase in T-cells in IL-7-infected FSA compared with control tumors. CD8+ T-cells were particularly elevated, but CD4+ lymphocytes were also increased in number, as were eosinophils and basophils. The CD4+:CD8+ ratio in IL-7-infected FSA was 1:1.7 in comparison to 1:0.6 in control tumors. Lymphocytes isolated from IL-7-producing tumors had greatly enhanced cytotoxicity towards uninfected, parental FSA cells. Killing of non-cross-reacting fibrosarcoma line was also increased but to a much lesser extent.

Injection of recombinant human IL-7 directly into established FSA tumors slowed their growth and, in a significant number of instances, caused complete regression. Mice that had rejected tumor became specifically immune. The dose that was needed for this effect was, however, somewhat large: 20 µg twice daily for 10 days. This result contrasts with the efficacy of IL-7 gene infection in stimulating responses to the same tumor. These considerations make IL-7 a good candidate for tumor-directed cytokine gene therapy.

¹ This work was supported by grants from the National Cancer Institute, the British Columbia Health Care Research Foundation, and the National Cancer Institute of Canada. G. J. D. is a National Cancer Institute of Canada Career Scientist.

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, UCLA School of Medicine, University of California, Los Angeles, Los Angeles, CA 90024-1714.

Received 12/16/91. Accepted 5/ 5/92.

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