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Departments of Medicine [K. C., Y. F., C. M. T., G. S., H. E. B., K. C.], Medical and Molecular Genetics [K. C.], Microbiology/Immunology [S. B., H. E. B., K. C.], Surgery [E. A. W.], and the Walther Oncology Center [S. B., J. G., H. E. B.], Indiana University School of Medicine, Indianapolis, Indiana 46202, and the Immunex Corporation, Seattle, Washington [S. L.]
Flt3-Ligand (Flt3-L) is a stimulatory cytokine for a variety of hematopoietic lineages, including dendritic cells and B cells. The antitumor properties of Flt3-L were evaluated in C3H/HeN mice challenged with the syngeneic C3L5 murine breast cancer cell line. Eighty % of animals receiving 500 µg/kg/day of Chinese hamster ovary-derived human Flt3-L for 10 days were protected from tumor growth, whether the tumor challenge was administered on the first or fourth days of Flt3-L administration. The protection provided by soluble Flt3-L was transient. All tumor-free animals rechallenged 4 weeks after the primary challenge developed tumor. Transduction of C3L5 with retroviral vectors expressing human or murine Flt3-L did not influence in vitro growth or MHC expression but decreased in vivo tumor development to 0 and 10% of mice, respectively. This compares with tumor growth of 52% with interleukin-2 transduced C3L5 and over 85% with untransduced and control vector-transduced C3L5. Unlike animals treated with soluble Flt3-L, administration of Flt3-L as a tumor vaccine protected mice from a subsequent challenge with untransduced C3L5 in 60–78% of mice, compared to 0% of controls. Our initial work used the most common Flt3-L isoform, which is membrane bound but can undergo proteolytic cleavage to generate a soluble form. To evaluate the role of the various Flt3-L isoforms in preventing tumor formation, retroviral vectors encoding only the membrane-bound form or only the soluble isoform were evaluated in the C3L5 model. Tumor formation was similar with either isoform, preventing tumor formation in 80–90% of mice after the primary challenge and 88–89% after the secondary challenge. Splenocytes obtained 4 weeks after the secondary challenge conferred adoptive immunity to naive mice in 60% of animals. This initial report of antitumor activity by Flt3-L is consistent with its known stimulatory effect on antigen-presenting cells and suggests it may enhance the development of tumor vaccines.
1 This work was supported by a Breast Cancer Research Grant from the Catherine Peachy Foundation and Public Health Service Grant PO1 CA59348 (to K. C.). Support (to H. E. B.) includes USPHS Grants R01 HL54037, R01 HL56416, and a project on P01 HL 53586. During the course of this work, S. B. was supported by NIH training program T32 DK07519 (to H. E. B.) and is currently a Fellow of the Leukemia Society of America, Inc.
2 To whom requests for reprints should be addressed, at the Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, IB442, 975 West Walnut Street, Indianapolis, IN 46202. Phone: (317) 274-0843; Fax: (317) 274-0396.
Received 3/ 7/97. Accepted 6/11/97.
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