Flt3-ligand induces transient tumor regression in an ectopic treatment model of major histocompatibility complex-negative prostate cancer.
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 > or =80% of the mice had palpable TRAMP-C1 tumors. Treatment with Flt3-L at 10 microg/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 microg/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 mphi. In regressor nice, 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-gamma 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.
Ciavarra
R P
RP
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk 23501, USA. rpc@borg.evms.edu
Somers
K D
KD
Brown
R R
RR
Glass
W F
WF
Consolvo
P J
PJ
Wright
G L
GL
Schellhammer
P F
PF
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007150:Immunohistochemistry; D007167:Immunotherapy; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000473:pathology; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051381:Rats; D012074:Remission Induction; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C084881:flt3 ligand protein; D007371:Interferon-gamma