Concurrent administration of granulocyte colony-stimulating factor or granulocyte-monocyte colony-stimulating factor enhances the biological activity of rituximab in a severe combined immunodeficiency mouse lymphoma model.
A predominant percentage of the in vivo antitumor activity of rituximab occurs through antibody-dependent cellular cytotoxicity (ADCC) via FcgammaRIII receptors. Co-expression of CD11b/CD18 (MAC-1), an adhesion molecule present in activated neutrophils, plays an important role in the induction of ADCC. The effects of granulocyte-monocyte colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on the biological activity of rituximab were studied in a non-Hodgkin's lymphoma (NHL)-bearing severe combined immunodeficiency (SCID) mouse model. Natural killer (NK) cell-depleted SCID mice were inoculated intravenously with Raji cells. Animals were divided into 6 cohorts: group A: placebo (saline injection); group B: murine (m)-G-CSF; group C: m-GM-CSF; group D: rituximab alone; group E: concurrent m-G-CSF and rituximab; and group F: concurrent m-GM-CSF and rituximab. Treatment with G-CSF or GM-CSF led to a 1.5- to 2-fold increase of CD11b/CD18 expression in neutrophils. Treatment with G-CSF led to the highest expression of CD11b/CD18 on neutrophils. No antitumor activity was observed among mice treated with G-CSF or GM-CSF alone. After 3 months, survival rates were highest in animals treated with rituximab and G-CSF (53.3%) compared to rituximab alone (13.3%) or in combination with peg-GM-CSF (26.7%). Increasing neutrophil counts via cytokine stimulation may play an important role in augmenting rituximab-associated antitumor activity.
Hernandez-Ilizaliturri
Francisco J
FJ
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Jupudy
Venkata
V
Reising
Scott
S
Repasky
Elizabeth A
EA
Czuczman
Myron S
MS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology; D008223:Lymphoma / Q000188:drug therapy* / Q000209:etiology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000382:microbiology; D011994:Recombinant Proteins; D000069283:Rituximab; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069283:Rituximab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor