TY - JOUR
T1 - Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma
AU - Mastrangelo, Michael J.
AU - Maguire, Henry C.
AU - Eisenlohr, Laurence C.
AU - Laughlin, Carol E.
AU - Monken, Claude E.
AU - McCue, Peter A.
AU - Kovatich, Albert J.
AU - Lattime, Edmund C.
N1 - Funding Information:
We thank Debbie Cole for secretarial services and Margaret McCormick and Nicole Eckholm for expert technical assistance. The work performed by C.E.L. in constructing the vaccinia/GM-CSF recombinant was the basis of her Master’s thesis. This work was supported by grants from the American Cancer Society (no. EDT-98 and no. IM-742), the National Institutes of Health (R21-CA69253, R01-CA42908, and R01-CA59568), and the Nat Pincus Trust.
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
KW - Gene therapy, melanoma
KW - Intratumoral
KW - Recombinant GM-CSF
KW - Vaccinia
UR - http://www.scopus.com/inward/record.url?scp=0033193127&partnerID=8YFLogxK
U2 - 10.1038/sj.cgt.7700066
DO - 10.1038/sj.cgt.7700066
M3 - Article
C2 - 10505851
AN - SCOPUS:0033193127
SN - 0929-1903
VL - 6
SP - 409
EP - 422
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
IS - 5
ER -