R E V I E W Clinical uses of GM-CSF, a critical appraisal and update Martha Arellano Sagar Lonial Emory University, Winship Cancer Institute, Atlanta, GA, USA Correspondence: Martha Arellano Emory University,Winship Cancer Institute, 1365C Clifton Road, Suite C2068,Atlanta, Georgia, USA 30322 Email martha.arellano@emoryhealthcare. org Abstract: The role of granulocyte-macrophage-colony-stimulating factor (GM-CSF) in the supportive care of cancer patients has been evaluated with promising results. More recently, GM-CSF has been added to regimens for the mobilization of hematopoietic progenitor cells. An expanding role for GM-CSF in regulating immune responses has been recognized based upon its activity on the development and maturation of antigen presenting cells and its capa- bility for skewing the immune system toward Th1-type responses. GM-CSF has been shown to preferentially enhance both the numbers and activity of type 1 dendritic cells (DC1), the subsets of dendritic cells responsible for initiating cytotoxic immune responses. The increase in DC1 content and activity following local and systemic GM-CSF administration support a role for GM-CSF as an immune stimulant and vaccine adjuvant in cancer patients. GM-CSF has shown clinical activity as an immune stimulant in tumor cell and dendritic cell vaccines, and may increase antibody-dependent cellular cytotoxicity. The successful use of myeloid act- ing cytokines to enhance anti-tumor responses will likely require the utilization of GM-CSF in combination with cytotoxic or other targeted therapies. Keywords: GM-CSF, G-CSF, cancer, hematopoietic cytokines Introduction/background Granulocyte-macrophage-colony-stimulating factor (GM-CSF) and granulocyte- colony-stimulating factor (G-CSF) belong to the family of hematopoietic cyto- kines. Their activities include stimulating the proliferation of granulocyte and/or macrophage progenitor cells, inﬂuencing differentiation, inducing maturation, and stimulating the functional activity of mature hematopoietic cells (Inaba et al 1992; Metcalf and Nicola 1995; Metcalf 1998). Colony stimulating factors (CSF) are not only important as mediators of the cellular response to immunologic or infectious insults but are also essential for maintaining basal hematopoiesis (Dranoff et al 1994; Fantuzzi 2003). G-CSF-deﬁcient mice manifest a chronic neutropenia and an impaired response to infectious challenge leading to premature death (Lieschke et al 1994). GM-CSF-deﬁcient mice, on the other hand, have normal levels of steady-state blood cell production, but exhibit defective phagocytosis and decreased oxygen radical production by granulocytes and macrophages; responses which are essential for the anti-bacterial defense (Stanley et al 1994; Zhan et al 1998; LeVine et al 1999). These mice also exhibit decreased tumor necrosis factor-alpha and leukotriene secretion, abnormal para-bronchial accumulations of B and T lympho- cytes, and decreased catabolism of alveolar surfactant lipids and proteins leading to a syndrome reminiscent of pulmonary alveolar proteinosis (Stanley et al 1994; Paine et al 2001). Double G-CSF and GM-CSF knockout mice exhibited a greater degree of neutropenia, and had an increased mortality rate in the early post-natal period compared to mice deﬁcient in G-CSF alone (Seymour et al 1997). Enzler et al (2003) found that mice deﬁcient in GM-CSF and gamma interferon (IFN-γ) Biologics: Targets & Therapy 2008:2(1) 13–27 © 2008 Dove Medical Press Limited. All rights reserved 13