Research

Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas

Hideho Okada^1,2,8 , Frank S Lieberman^3,8 , Kevin A Walter^1,6,8 , L Dade Lunsford^1,8 , Douglas S Kondziolka^1,8 , Ghassan K Bejjani¹ , Ronald L Hamilton^6,8 , Alejandro Torres-Trejo^3,8 , Pawel Kalinski^2,4 , Quan Cai² , Jennifer L Mabold⁸ , Howard D Edington² , Lisa H Butterfield^2,4,5 , Theresa L Whiteside⁶ , Douglas M Potter⁷ , S Clifford Schold Jr³ and Ian F Pollack^1,8

¹  Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

²  Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

³  Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

⁴  Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

⁵  Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

⁶  Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

⁷  Biostatistics Department, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA

⁸  Brain Tumor Program, University of Pittsburgh Cancer Institute (UPCI), Pittsburgh, PA, USA

author email corresponding author email

Journal of Translational Medicine 2007, 5:67doi:10.1186/1479-5876-5-67

Published:	19 December 2007

Abstract

Background

The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL)-4 gene transfected fibroblasts.

Methods

In University of Pittsburgh Cancer Institute (UPCI) protocol 95-033, adult participants with recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) received gross total resection (GTR) of the recurrent tumors, followed by two vaccinations with autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector admixed with irradiated autologous glioma cells. In UPCI 99-111, adult participants with newly diagnosed GBM or AA, following GTR and radiation therapy, received two intradermal vaccinations with the TFG-IL4-Neo-TK-transfected fibroblasts admixed with type-1 dendritic cells (DC) loaded with autologous tumor lysate. The participants were evaluated for occurrence of adverse events, immune response, and clinical response by radiological imaging.

Results and Discussion

In UPCI 95-033, only 2 of 6 participants received the vaccinations. Four other participants were withdrawn from the trial because of tumor progression prior to production of the cellular vaccine. However, both participants who received two vaccinations demonstrated encouraging immunological and clinical responses. Biopsies from the local vaccine sites from one participant displayed IL-4 dose-dependent infiltration of CD4⁺ as well as CD8⁺ T cells. Interferon (IFN)-γ Enzyme-Linked Immuno-SPOT (ELISPOT) assay in another human leukocyte antigen (HLA)-A2⁺ participant demonstrated systemic T-cell responses against an HLA-A2-restricted glioma-associated antigen (GAA) epitope EphA2_883–891. Moreover, both participants demonstrated clinical and radiological improvement with no evidence of allergic encephalitis, although both participants eventually succumbed with the tumor recurrence. In 99-111, 5 of 6 enrolled participants received scheduled vaccinations with no incidence of major adverse events. Monocyte-derived DCs produced high levels of IL-12 p70. Treatment was well tolerated; however, we were unable to observe detectable IFN-γ post-vaccine responses or prolonged progression-free survival in these participants.

Conclusion

Feasibility challenges inherent in the generation of a patient-specific gene transfection-based vaccine strongly suggests the need for more practical formulations that would allow for the timely administration of vaccines. Nevertheless, successful generation of type-1 DCs and preliminary safety in the current study provide a strong rationale for further efforts to develop novel glioma vaccines.