Pilot study of Flt3 ligand comparing intraperitoneal with subcutaneous routes on hematologic and immunologic responses in patients with peritoneal carcinomatosis and mesotheliomas.
OBJECTIVE
This study compared the clinical toxicity and hematological effects of i.p. and s.c. administration of fms-like tyrosine kinase-3-ligand (Flt3-L; Amgen, Thousand Oaks, CA), a truncated glycoprotein that increases dendritic cells (DCs) and monocytes.


METHODS
Patients with peritoneal carcinomatosis or mesothelioma were randomly assigned to treatment with Flt3-L (25 micro g/kg, maximum 1500 micro g), i.p. or s.c., days 1-5 and 8-12, then changed to the alternative route at 4 weeks. Treatment was continued s.c. or i.p. at 8 weeks.


RESULTS
Fifteen patients (14 evaluable) were randomized to receive i.p. (n = 8) or s.c. (n = 7) injections. Their median age was 55 years (range, 40-68 years). Primary tumors were as follows: ovarian/peritoneal cancer (n = 9); gastrointestinal cancer (n = 2); and mesothelioma (n = 4). Treatment was well tolerated without serious toxicity (24 i.p. cycles; 32 s.c. cycles). Treatment (i.p. or s.c.) resulted in significant increases in WBCs (WBC, monocytes, and Lin(-)DR(+) DCs), and platelets (during washout). Both interleukin (IL)-12(p70) and IL-10 were secreted by monocyte-derived DCs after in vitro exposure to maturation factors. Increased IL-12 versus IL-10 secretion responses and higher proportions of the CD11c(+) DC subset in post-Flt3-L specimens suggested a maturational shift toward the monocyte-derived DC phenotype had occurred. Three patients (2 with mesothelioma and 1 with gastrointestinal cancer) had stable disease for 8, 8, and 12+ months, respectively.


CONCLUSIONS
Flt3-L, administered either i.p. or s.c., is well tolerated and produced similar increases in monocytes, DCs, and platelets. DCs from peripheral blood and peritoneal fluids showed cell surface phenotypic and cytokine maturational responses to activation stimuli. These findings suggested that Flt3-L, in combination with suitable activating agents, could be developed further in patients with epithelial ovarian cancer.
Freedman
Ralph S
RS
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. rfreedma@mdanderson.org
Vadhan-Raj
Saroj
S
Butts
Cherie
C
Savary
Cherylyn
C
Melichar
Bohuslav
B
Verschraegen
Claire
C
Kavanagh
John J
JJ
Hicks
Marshall E
ME
Levy
Lawrence B
LB
Folloder
Jody K
JK
Garcia
Michael E
ME
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D006403:Hematologic Tests; D006801:Humans; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage*; D008654:Mesothelioma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D010865:Pilot Projects
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D016207:Cytokines; D008565:Membrane Proteins; C084881:flt3 ligand protein