Technical hurdles in a pilot clinical trial of combined B7-2 and GM-CSF immunogene therapy for glioblastomas and melanomas.
OBJECTIVE
Malignant glioblastomas and melanomas continue to have a dismal prognosis despite advances in conventional therapy. This has led to investigations of novel treatment strategies including immunogene therapy. We report a pilot clinical trial of combined B7-2 and GM-CSF immunogene therapy for gliomas and melanomas and discuss technical hurdles encountered.


METHODS
Patients with recurrent malignant gliomas or medically refractory melanomas were vaccinated with irradiated autologous tumor cells transduced with B7-2 and GM-CSF genes using a retroviral vector. Patients were monitored for toxicity, inflammatory/immune reactions, and clinical status.


RESULTS
Vaccine preparation was attempted from 116 malignant glioma and 32 melanoma specimens. Adequate vaccines could only be prepared for five glioblastoma and three melanoma patients. Six patients (three recurrent glioblastomas and three melanomas) were actually vaccinated. Minor toxicities included flu-like symptoms (3/6), injection site erythema (4/6), and asymptomatic elevations in liver enzymes (3/6). Most patients showed evidence of an inflammatory response but specific anti-tumor immunity was not demonstrated. All six patients have died, although three patients with minimal residual disease at treatment had prolonged recurrence-free intervals after vaccination.


CONCLUSIONS
Combined B7-2 and GM-CSF immunogene therapy for glioblastomas and melanomas using autologous tumor cells has many technical pitfalls hindering large scale application and evaluation. As a result, this pilot study was too limited to draw meaningful conclusions regarding safety or anti-tumor immunity. While immunotherapy has been promising in pre-clinical studies, alternate strategies will be required to bring these benefits to patients.
Parney
Ian F
IF
Department of Clinical Neurosciences, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada. ian.parney@calgaryhealthregion.ca
Chang
Lung-Ji
LJ
Farr-Jones
Maxine A
MA
Hao
Chunhai
C
Smylie
Michael
M
Petruk
Kenneth C
KC
D000328:Adult; D051940:B7-2 Antigen / Q000235:genetics* / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007125:Immunogenetics / Q000379:methods; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D010865:Pilot Projects; D012190:Retroviridae; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic
D051940:B7-2 Antigen; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor