Arellano and Lonial acquired lymphoproliferative disorders and solid tumors in a background of chronic inﬂammation, supporting the relationship between inﬂammation and carcinogenesis. Recombinant GM-CSF has made signiﬁcant contribu- tions in the supportive care of cancer patients, owing to enhanced myeloid recovery after cytotoxic chemotherapy. Recently GM-CSF has been successfully included in mobi- lization regimens for hematopoietic progenitor cell trans- plantation (Cashen et al 2004; Lonial et al 2004). Recent data on the effects of GM-CSF on dendritic cells has led to growing interest in its use as primary immunotherapy. The ability of GM-CSF to generate of type 1 dendritic cells (DC1), which can skew T-cells toward a Th-1 phenotype has been demonstrated and is an attractive approach toward generating anti-tumor effects (Ferlazzo et al 2000). Periph- eral blood mononuclear cells (PBMC), T-cells and antigen presenting cells (APC) cultured with GM-CSF exhibited increased production of type 1 cytokines (interleukin-12, interferon-alpha, tumor necrosis factor-alpha) and decreased production of type 2 cytokines (interleukin-4 and interleu- kin-10) compared to cells treated with control media or G-CSF (Eksioglu et al 2007). In addition, APC treated with GM-CSF induced higher proliferation of allogeneic T-cells compared to APC treated with G-CSF or control media (Eksioglu et al 2007). The capacity of GM-CSF to skew the immune system toward Th1 effects in vitro suggests a role for GM-CSF in cell-mediated immune therapy and is cur- rently being tested in-vivo. Dendritic cells (DC) have come to be recognized as the sensors of tissue injury, infection, or malignant transformation and as the agents responsible for the initial activation of the immune response (Matzinger 1994). DC are the antigen presenting cells of the immune system, have the capacity to express both HLA class I and HLA class II restricted peptides, and express the co-stimula- tory molecules needed for T-cell activation (Banchereau et al 2000). A number of reports have shown that administration of GM-CSF can induce anti-tumor immune responses and tumor regressions. These immune activities are attributed to the action of GM-CSF on DC (Dranoff et al 1993; Wos et al 1996; Davidson et al 1998). The limitations of GM-CSF as an immune adjuvant, and its modest clinical activity, have been attributed to discordance between the observed immune response measured in the laboratory and the clinical correlates of anti-tumor activity. The need to generate the co- stimulatory signals required to break immune tolerance, the proper dosing and timing of cytokines, the state of disease at time of treatment, and the role of concomitant chemotherapy are the topics of current investigation. In this review, we will 14 discuss the role of GM-CSF as primary treatment and as an immune adjunct to the therapy of cancer. Relationship between cancer and inﬂammation The connection between inflammation and malignant transformation has been recognized for over a century. In 1863, Dr. Rudolf Virchow recognized a possible relation- ship between chronic inﬂammation and the development of cancer, based on observations of inﬂammatory inﬁltrates and spontaneous regression of malignant tumors (Balkwill and Mantovani 2001; Schreiber 2003). In the late 1890s, William Coley, a surgeon in New York, observed tumor regressions in patients with cancer who recovered from acute skin infec- tions. He then developed a vaccine composed of extracts of inactivated bacteria, which he administered to cancer patients with variable results (Nauts et al 1953). He observed that tumor regressions were more common among patients who developed both a local and a systemic inﬂammatory response (Hoption Cann et al 2002). The premise was that non-speciﬁc activation of the immune system could lead to (speciﬁc) cytokine-mediated anti-tumor effects. While cytokines are credited with potent anti-tumor effects, a counteracting effect of tumor-secreted cytokines, and tumor-associated tolerizing T-cells, or immature DC has also been documented (Perrot et al 2007; Wang and Wang 2007). Some solid tumors, for example, are capable of inducing immune tolerance via down-regulation of antigen-speciﬁc T-cell responses by tolerigenic APC (Cuenca et al 2003). Immature tumor-inﬁl- trating DC are capable of compromising the tumor-speciﬁc immune response in draining lymph nodes (Perrot et al 2007). The premise that the immune system can be manipulated in vivo supports a role for the manipulation of the cytokine/co- stimulatory signal milieu in the treatment of cancer using recombinant cytokines, such as GM-CSF. Approaches will need to account for the level of maturation of tumor- associated DC, and the number of tumor-associated regulatory T-cells GM-CSF may enhance tumor-speciﬁc antigen presenta- tion leading to better recognition of tumors by the immune system via effects on DC. However, its beneﬁt has been limited to patients with minimal residual disease, and dose- escalation has been limited by signiﬁcant systemic toxici- ties. The optimal use of cytokines may be directly in the tumor micro-environment. Furthermore, better quantitative Biologics:Targets & Therapy 2008:2(1)