Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma

Michael J. Mastrangelo, Henry C. Maguire, Laurence C. Eisenlohr, Carol E. Laughlin, Claude E. Monken, Peter A. McCue, Albert J. Kovatich, Edmund C. Lattime

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261 Scopus citations

Abstract

Seven immunocompetent, revaccinated patients with surgically incurable cutaneous melanoma underwent treatment of dermal and/or subcutaneous metastases with twice-weekly intratumoral injections of escalating doses (104-2 × 107 plaque-forming units (PFU)/lesion; 104-8 × 107 PFU/session) of a vaccinia/GM-CSF recombinant virus for 6 weeks. Patients with stable or responding disease were maintained on treatment until tumor resolution or progression. Systemic toxicity was infrequent, dose-related, and limited to mild flu-like symptoms that resolved within 24 hours. Local inflammation, at times with pustule formation, was consistently seen with doses of ≥107 PFU/lesion. Chronically treated lesions showed a dense infiltration, with CD4+ and CD8+ lymphocytes, histiocytes, and eosinophils. All seven patients developed an antivaccinia humoral immune response 14-21 days following revaccination. Despite the presence of these antivaccinia antibodies, the reporter gene was expressed, as judged by the development of anti-β-galactosidase antibodies in all patients. Passenger cytokine gene function was evidenced by the presence of virally encoded GM-CSF mRNA at injection sites both early (weeks 1 and 5) and late (week 31) in the course of treatment. Eosinophilia at treatment sites indicated that physiologically significant levels of functional cytokine were generated. However, there were no changes in the total number of peripheral white blood cells or in the numbers or percentages of polymorphonuclear leukocytes, monocytes, or eosinophils. GM-CSF was not detected in the sera. The two patients with the largest tumor burdens failed to respond even at treatment sites. Three patients had mixed responses, with regression of treated and untreated dermal metastases and progression of disease elsewhere. One patient had a partial response, with regression of injected and uninjected regional dermal metastases. Residual melanoma was excised, rendering the patient disease free. One patient with only dermal metastases confined to the scalp achieved a complete remission. Sequential administration of escalating doses of a GM-CSF recombinant vaccinia virus is safe, effective at maintaining passenger gene function, and can induce tumor regression.

Original languageEnglish (US)
Pages (from-to)409-422
Number of pages14
JournalCancer gene therapy
Volume6
Issue number5
DOIs
StatePublished - Jan 1 1999

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Keywords

  • Gene therapy, melanoma
  • Intratumoral
  • Recombinant GM-CSF
  • Vaccinia

Cite this

Mastrangelo, M. J., Maguire, H. C., Eisenlohr, L. C., Laughlin, C. E., Monken, C. E., McCue, P. A., Kovatich, A. J., & Lattime, E. C. (1999). Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer gene therapy, 6(5), 409-422. https://doi.org/10.1038/sj.cgt.7700066