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Granulocyte-Macrophage Colony-Stimulating Factor: Another Cytokine With Adjuvant Therapeutic Benefit in Melanoma?

Emory University, Atlanta, GA

John M. Kirkwood, MD

University of Pittsburgh, Pittsburgh, PA

INTERFERON ALFA-2b (IFN-2b) and interleukin-2 (IL-2) are immunomodulatory cytokines that have been studied intensively as therapeutic biologic agents for melanoma in the past 20 years. On the basis of randomized controlled trial data, IFN-2b was approved as the first effective adjuvant therapy for melanoma.¹ More recently, IL-2 was approved for therapy of metastatic melanoma on the basis of uncontrolled trials in which a small fraction (6%) of patients with metastatic disease were shown to have durable complete remissions.² To date, the mechanism of these two therapies has eluded careful studies in many laboratories. Evidence favors an immunologic basis, ie, the enhancement of specific immune recognition of tumor mediated either at the level of tumor cell antigen expression and processing or at the level of the host effector cells. IFN-2b regulates histocompatibility antigen expression and may augment antigen-presenting cell function as well as alter the distribution of CD4:8 T-cell populations and the Th1/Th2 bias of immune response. IL-2 is a major growth factor and the second signal for antigen-primed T-cell proliferation. In the absence of a clear understanding of the operative mechanism of these biologic agents, the development of optimal dosing regimens and the selection of the most responsive populations for therapy have been difficult. The development of combined-modality approaches has been a further problem, since studies have failed to show compelling evidence of synergism even though these agents may be additive or perhaps even synergistic with vaccines.^3-5 Current intergroup cooperative trials sponsored by the National Cancer Institute through the Eastern Cooperative Oncology Group (ECOG) and the Southwest Oncology Group seek to demonstrate a curative advantage of these biologic agents in conjunction with polychemotherapy, compared with polychemotherapy alone.

The article by Spitler et al appearing in this issue of the Journal of Clinical Oncology⁶ adds suggestions that a widely available, less toxic hemopoietic growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), may have adjuvant benefit in melanoma. Early work with GM-CSF demonstrated its ability to increase the number of cells of the monocyte/macrophage series in cancer patients⁷ and to enhance their ability to lyse tumor cells, including melanoma.^8,9 The recent demonstration of a role for GM-CSF in the growth and maturation of dendritic cells has thrust GM-CSF onto center stage in efforts to modulate antigen-presenting cells for effective immunization, as opposed to the tolerance that may result from antigenic stimulation.^10,11 Evidence suggesting a benefit of GM-CSF has come from trials of vaccination with tumor cells transduced with the gene for GM-CSF, both in murine models and in humans. In two separate melanoma models, GM-CSF was found to be the most effective of the multiple cytokines studied for induction of long-term protective immunity.^12,13 A phase I human trial using irradiated autologous melanoma cells engineered to secrete GM-CSF demonstrated marked immune responses; metastases from 11 of 16 patients examined exhibited dense infiltration with T lymphocytes and plasma cells associated with tumor cell destruction, fibrosis, and edema remote from the transferred cells.¹⁴ Although only one of 21 assessable patients had a partial response in classical terms, resected tumor nodules in several others demonstrated fibrosis and immune cell infiltrates attributed to the GM-CSF–transduced tumor cell therapy.

GM-CSF has been studied as an immunologic adjuvant in several vaccination protocols designed to elicit immune responses against "self" antigens,^15-18 including lineage differentiation antigens associated with the melanosome, of relevance to adjuvant applications in melanoma.^19,20 How it will ultimately compare to other cytokines is not yet clear.²¹ GM-CSF has not been exhaustively evaluated as a single agent for systemic therapy of metastatic stage IV melanoma, but all available information is negative.^21-23 There are intriguing reports of intralesional antitumor activity of GM-CSF^24,25 and of inhalational administration of this cytokine for pulmonary metastatic disease.²⁶ Animal studies suggest a possible antiangiogenic role for GM-CSF.²⁷ These areas require further investigation.

Spitler et al⁶ studied the benefit of GM-CSF in patients at high or very high risk of relapse and death with stage III or IV melanoma who were rendered free of disease by surgery. Forty-eight patients were treated with GM-CSF 125 µg/m² on a cyclic program of 14 days on treatment and 14 days off treatment. Their survival was compared with that of patients drawn from the University of Alabama melanoma database and reported to be superior. The obvious criticisms of the study are that the trial is small and relies on historical controls from a remote era. One must, therefore, temper any conclusions, recognizing that the prognosis of patients who have simply been observed in the context of two recent adjuvant studies of the ECOG (E1684) and the United States Melanoma Intergroup (E1690) differ by more than the difference of any reported therapy in melanoma and are significant in terms of both relapse interval and survival (P2 = .001 for survival differences between observation arms of E1690 and E1684).²⁸ Despite the increasing prognostic precision of new surgical techniques, such as sentinel node mapping, and the improved sensitivity and specificity of new radiologic imaging tools for the assessment of metastatic disease, the era of historically controlled trials is past.

No correlative immunologic evaluation was performed in the study of Spitler et al.⁶ The intriguing evidence of vaccine immunopotentiation by GM-CSF and the well-described array of T-cell targets that are candidate intermediate end points for clinical trials in melanoma, along with the data reviewed above, support more extensive evaluation of the possible immune effects of GM-CSF in this setting.

The ECOG, the North Central Cancer Treatment Group, and the National Cancer Institute of Canada have initiated intergroup trial E4697 to evaluate the ability of GM-CSF to improve overall survival and time to progression in patients at very high risk of recurrent melanoma who were rendered free of disease by surgery. Eligible patients are those with clinically evident satellite or in-transit melanoma, nodal disease with gross extracapsular extension, or stage IV disease that is completely resectable. In a subset of patients, this trial has been designed to also evaluate the role of vaccination against three melanoma-associated peptide antigens derived from the tyrosinase, gp-100, and Melan-A/MART-1 molecules. Because T-cell recognition of these peptide antigens is restricted by HLA-A2, only patients who express HLA-A2 will be eligible for the multiepitope peptide vaccine. HLA-A2–negative patients will be randomized to receive either GM-CSF 250 µg subcutaneously daily for 14 days every 28 days or placebo. Patients who are HLA-A2–positive will be randomized between GM-CSF, peptide vaccination, GM-CSF plus peptide vaccination, or placebo. Six hundred patients are planned to be enrolled (100 patients/arm) to give sufficient power for comparisons of GM-CSF versus no GM-CSF in all patients and of the multiepitope peptide vaccination versus no vaccination in HLA-A2–positive patients.

As stated by Spitler et al, it is too soon to draw conclusions in regard to the therapeutic efficacy of GM-CSF in high-risk melanoma from their study.⁶ Interest in GM-CSF is drawn equally from its potential effects upon antigen-presenting cells as a means to enhance effective immunity over immunologic tolerance, its potential use in conjunction with vaccines, and its lower toxicity profile in comparison to immunologic agents currently approved for use in melanoma (high-dose IFN-2b in high-risk resectable melanoma and high-dose IL-2 in metastatic melanoma). The therapeutic and immunologic functions of this interesting cytokine deserve further study.

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