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Flt3-Ligand Induces Transient Tumor Regression in an Ectopic Treatment Model of Major Histocompatibility Complex-negative Prostate Cancer¹

Departments of Microbiology and Molecular Cell Biology [R. P. C., K. D. S., R. R. B., P. J. d. C., G. L. W.], Pathology and Anatomy [W. F. G.], and Urology [P. F. S.], and Virginia Prostate Center [G. L. W., P. F. S.], Eastern Virginia Medical School, Norfolk, Virginia 23501, and Sentara Cancer Center, Norfolk, Virginia 23501 [G. L. W., P. F. S.]

We assessed the in vivo efficacy of Flt3-ligand (Flt3-L) treatment in C57BL/6 mice bearing a well-established MHC class I-negative prostate carcinoma TRAMP-C1. Flt3-L immunotherapy was initiated approximately 30 days after tumor inoculation, a time when 80% of the mice had palpable TRAMP-C1 tumors. Treatment with Flt3-L at 10 µg/day for 21 consecutive days suppressed TRAMP-C1 tumor growth and induced tumor stabilization (P = 0.0337). Enhanced tumor regression was demonstrated at a higher dose of 30 µg/day (P < 0.0001). Tumors excised from mice treated with Flt3-L were smaller than carrier-treated controls and contained a more pronounced mixed inflammatory cell infiltrate primarily composed of m. In regressor mice, tumors reappeared at the site of injection when Flt3-L therapy was terminated. When the experiment was repeated with MHC class I-positive TRAMP-C1 cells, tumor stabilization and/or regression was again observed after treatment (P < 0.0001); however, once again, tumors reappeared after the termination of therapy despite an extended treatment schedule (35 days). MHC class I-negative variants were present in tumors isolated from carrier- and Flt3-L-treated mice, and this phenotype could be reversed by IFN- treatment in vitro. Thus, Flt3-L treatment of mice with preexisting transplantable prostate tumors results in tumor regression that is dose-dependent and accompanied by a pronounced mixed-cell inflammatory tumor infiltrate. However, disease relapse was invariably observed after the termination of therapy, which suggests that Flt3-L treatment of advanced MHC^- prostate cancers will require adjuvant modalities to achieve a durable response.

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