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Clinical uses of GM-CSF, a critical appraisal and update.

Arellano M, Lonial S - Biologics (2008)

Bottom Line: 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.The successful use of myeloid acting cytokines to enhance anti-tumor responses will likely require the utilization of GM-CSF in combination with cytotoxic or other targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Emory University, Winship Cancer Institute, Atlanta, GA, USA.

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 capability 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 acting cytokines to enhance anti-tumor responses will likely require the utilization of GM-CSF in combination with cytotoxic or other targeted therapies.

No MeSH data available.


Related in: MedlinePlus

GM-CSF and IFN may upregulate co-stimulatory molecule expression on leukemic blasts leading to stimulation of cytotoxic T-cells and a GVL effect.Abbreviations: APC, antigen presenting cells; GVL, graft versus leukemia; GM-CSF, granulocyte-macrophage-colony-stimulating factor; IFN, interferon; CTL, cytotoxic T lymphocyte.
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f1-btt-2-13: GM-CSF and IFN may upregulate co-stimulatory molecule expression on leukemic blasts leading to stimulation of cytotoxic T-cells and a GVL effect.Abbreviations: APC, antigen presenting cells; GVL, graft versus leukemia; GM-CSF, granulocyte-macrophage-colony-stimulating factor; IFN, interferon; CTL, cytotoxic T lymphocyte.

Mentions: Relapse of acute leukemia after allogeneic transplantation remains a significant therapeutic challenge, affecting approximately one third of all patients with acute leukemia who receive allogeneic transplantation as a curative therapy. Salvage post-transplant maneuvers have focused on utilization of second transplants, but these are limited to a minority (10% in most series) of fit patients. Clinical and pre-clinical data has suggested a role for cytokine therapy in the induction of graft versus leukemia effects in the setting of post-transplant relapse (Slavin et al 1996; Cortes et al 1998; Boyer et al 2000; Mohty et al 2002; Kolb et al 2004; Li and Waller 2004). Improving the antigen-presenting capacity of leukemic blasts may lead to clinically-significant anti-leukemic effects. The feasibility of generating DC-like leukemic antigen presenting cells upon treatment with cytokines, including GM-CSF has been demonstrated ( Santiago-Schwarz et al 1994; Mohty et al 2002). The level of co-stimulatory molecule expression on leukemic blasts has been hypothesized to play a role in the capacity of leukemic blasts to present antigen to effector cells (Vereecque et al 2000; Whiteway et al 2003). A retrospective study at our institution reviewing the treatment of acute leukemia relapsed after allogeneic transplantation revealed promising results among a minority of patients treated with GM-CSF and interferon-alpha-2b (Arellano et al 2007). A prospective clinical trial at our center is currently investigating the feasibility and activity of a regimen utilizing the combination of GM-CSF and interferon-alpha-2b after cytoreduction to treat acute leukemia relapsed after allogeneic transplantation. Correlative studies will test the hypothesis that GM-CSF and interferon-alpha-2b act by up-regulating co-stimulatory molecules on leukemic blasts, and down-regulating regulatory T-cells leading to improved antigen presentation and durable graft versus leukemia effects (Figure 1).


Clinical uses of GM-CSF, a critical appraisal and update.

Arellano M, Lonial S - Biologics (2008)

GM-CSF and IFN may upregulate co-stimulatory molecule expression on leukemic blasts leading to stimulation of cytotoxic T-cells and a GVL effect.Abbreviations: APC, antigen presenting cells; GVL, graft versus leukemia; GM-CSF, granulocyte-macrophage-colony-stimulating factor; IFN, interferon; CTL, cytotoxic T lymphocyte.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2727781&req=5

f1-btt-2-13: GM-CSF and IFN may upregulate co-stimulatory molecule expression on leukemic blasts leading to stimulation of cytotoxic T-cells and a GVL effect.Abbreviations: APC, antigen presenting cells; GVL, graft versus leukemia; GM-CSF, granulocyte-macrophage-colony-stimulating factor; IFN, interferon; CTL, cytotoxic T lymphocyte.
Mentions: Relapse of acute leukemia after allogeneic transplantation remains a significant therapeutic challenge, affecting approximately one third of all patients with acute leukemia who receive allogeneic transplantation as a curative therapy. Salvage post-transplant maneuvers have focused on utilization of second transplants, but these are limited to a minority (10% in most series) of fit patients. Clinical and pre-clinical data has suggested a role for cytokine therapy in the induction of graft versus leukemia effects in the setting of post-transplant relapse (Slavin et al 1996; Cortes et al 1998; Boyer et al 2000; Mohty et al 2002; Kolb et al 2004; Li and Waller 2004). Improving the antigen-presenting capacity of leukemic blasts may lead to clinically-significant anti-leukemic effects. The feasibility of generating DC-like leukemic antigen presenting cells upon treatment with cytokines, including GM-CSF has been demonstrated ( Santiago-Schwarz et al 1994; Mohty et al 2002). The level of co-stimulatory molecule expression on leukemic blasts has been hypothesized to play a role in the capacity of leukemic blasts to present antigen to effector cells (Vereecque et al 2000; Whiteway et al 2003). A retrospective study at our institution reviewing the treatment of acute leukemia relapsed after allogeneic transplantation revealed promising results among a minority of patients treated with GM-CSF and interferon-alpha-2b (Arellano et al 2007). A prospective clinical trial at our center is currently investigating the feasibility and activity of a regimen utilizing the combination of GM-CSF and interferon-alpha-2b after cytoreduction to treat acute leukemia relapsed after allogeneic transplantation. Correlative studies will test the hypothesis that GM-CSF and interferon-alpha-2b act by up-regulating co-stimulatory molecules on leukemic blasts, and down-regulating regulatory T-cells leading to improved antigen presentation and durable graft versus leukemia effects (Figure 1).

Bottom Line: 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.The successful use of myeloid acting cytokines to enhance anti-tumor responses will likely require the utilization of GM-CSF in combination with cytotoxic or other targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Emory University, Winship Cancer Institute, Atlanta, GA, USA.

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 capability 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 acting cytokines to enhance anti-tumor responses will likely require the utilization of GM-CSF in combination with cytotoxic or other targeted therapies.

No MeSH data available.


Related in: MedlinePlus