Technical hurdles in a pilot clinical trial of combined B7-2 and GM-CSF immunogene therapy for glioblastomas and melanomas
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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.
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.
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.
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.
Keywordscostimulation cytokine gene therapy glioblastoma immunotherapy melanoma
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- 3.Garrison M, Nathanson L, Prognosis and staging in melanomaSem Oncol; 23: 1996 725–733Google Scholar
- 5.Antonia SJ, B7-1 gene-modified tumor cell vaccinesCurr Opin Mol Therap 1999; 1:50–56Google Scholar
- 10.Parney IF, Petruk KC, Zhang C, Farr-Jones MA, Sykes DB, Chang L-J, GM-CSF and B7-2 combination immunogene therapy in an allogeneic hu-PBL-SCID/beige mouse – human glioblastoma multiforme modelHum Gene Therapy1997; 8:1073–1085Google Scholar
- 13.Yu JS, Burwick JA, Dranoff G, Breakefield XO, Gene therapy for metastatic brain tumors by vaccination with granulocyte-macrophage colony-stimulating factor-transduced tumor cellsHum Gene Therapy1997; 8:1065–1072Google Scholar
- 15.De Gast GC, Gallee MPW, Spits H, et al. Immunological, pathological, and long-term clinical data of vaccination with autologous granulocyte-macrophage colony-stimulating factor-transduced tumor cells in metastatic melanomaCancer Gene Ther 2000; 7:1204Google Scholar
- 18.Simons JW, Mikhak B, Chang J-F, et al. Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transferCancer Res1999; 59:195–204Google Scholar
- 26.Human gene marker/therapy clinical protocols (complete updated listing). Hum Gene Ther12: 2251–2337, 2001Google Scholar