Abstract
Several immunomodulatory checkpoint inhibitors have been approved for the treatment of patients with advanced melanoma, including ipilimumab, nivolumab and pembrolizumab. Talimogene laherparepvec is the first oncolytic virus to gain regulatory approval in the USA; it is also approved in Europe. Talimogene laherparepvec expresses granulocyte–macrophage colony-stimulating factor (GM-CSF), and with other GM-CSF-expressing oncolytic viruses in development, understanding the clinical relevance of this cytokine in treating advanced melanoma is important. Results of trials of GM-CSF in melanoma have been mixed, and while GM-CSF has the potential to promote anti-tumor responses, some preclinical data suggest that GM-CSF may sometimes promote tumor growth. GM-CSF has not been approved as a melanoma treatment. We undertook a systematic literature review of studies of GM-CSF in patients with advanced melanoma (stage IIIB–IV). Of the 503 articles identified, 26 studies met the eligibility criteria. Most studies investigated the use of GM-CSF in combination with another treatment, such as peptide vaccines or chemotherapy, or as an adjuvant to surgery. Some clinical benefit was reported in patients who received GM-CSF as an adjuvant to surgery, or in combination with other treatments. In general, outcomes for patients receiving peptide vaccines were not improved with the addition of GM-CSF. GM-CSF may be a valuable therapeutic adjuvant; however, further studies are needed, particularly head-to-head comparisons, to confirm the optimal dosing regimen and clinical effectiveness in patients with advanced melanoma.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1860-3) contains supplementary material, which is available to authorized users.
Highlights
Malignant melanoma accounts for approximately 1 % of cancer deaths worldwide, equating to over 55,000 deaths from this tumor type in 2012 [1]
A range of dosing schedules and routes of administration was used for granulocyte–macrophage colony-stimulating factor (GM-CSF), but GM-CSF was most often delivered by s.c. injection at a dose of 125–250 mg/m2
There was some evidence of clinical benefit in patients who received GM-CSF in combination with ipilimumab [49] or as part of a chemotherapy-containing regimen [52, 53, 56, 57, 59, 62]
Summary
Malignant melanoma accounts for approximately 1 % of cancer deaths worldwide, equating to over 55,000 deaths from this tumor type in 2012 [1]. Oncolytic viruses expressing GM-CSF have been developed, and in 2015, talimogene laherparepvec, a modified herpes simplex virus type 1, became the first oncolytic virus to gain regulatory approval in the USA, where it is indicated for the local treatment of unresectable cutaneous, subcutaneous (s.c.) and nodal lesions in patients with melanoma recurrent after initial surgery. In a model of liver metastases, expansion of MDSCs was dependent on tumor-produced GM-CSF [37] In contrast to these findings, a different model showed that GM-CSF administered in combination with peptide vaccines caused localized accumulation of DCs and tumor-specific T cells, but no significant increase in the proportion of MDSCs [38]. Analysis of tumor-infiltrating lymphocytes using a MART-1 ELIspot assay showed that talimogene laherparepvec induced a local antigen-specific effector T-cell response and systemic immunity against melanoma antigens. A protocol amendment was made at this stage and studies in which fewer than 10 patients received GM-CSF were excluded to focus the analysis on larger studies
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