Antitumor activity and immunotherapeutic properties of Flt3-ligand in a murine breast cancer model.
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 microg/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.
Chen
K
K
Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USA.
Braun
S
S
Lyman
S
S
Fan
Y
Y
Traycoff
C M
CM
Wiebke
E A
EA
Gaddy
J
J
Sledge
G
G
Broxmeyer
H E
HE
Cornetta
K
K
D019264:Adoptive Transfer; D000818:Animals; D016466:CHO Cells; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D006224:Cricetinae; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000517:prevention & control*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
D019496:Cancer Vaccines; D007376:Interleukin-2; D008565:Membrane Proteins; C084881:flt3 ligand protein