Recent Progress in Immunotherapy for Malignant Glioma: Treatment Strategies and Results from Clinical Trials

Abstract

An effective treatment paradigm for malignant gliomas may eventually require a multifaceted approach combining two or more different immunotherapeutic strategies. Such scenarios may involve the use of local cytokine gene therapy to enhance glioma-cell immunogenicity in conjunction with dendritic cell-based active vaccination to stimulate systemic tumoricidal T-cell immunity. Given the heterogeneity of this disease process and the potential risk of immunoediting out a selected, treatment-refractory tumor cell population, the concurrent use of multiple modalities that target disparate tumor characteristics may be of greatest therapeutic relevance.

Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy

“…Several animal models suggested that GBM may be amenable to immune therapeutic approaches (Sampson et al, 1996;Okada et al, 1998) and the identification of humoral as well as cellular immune responses in brain tumour patients triggered efforts to activate the immune system against glioma cells (Yu et al, 2001;Ueda et al, 2004). Although some encouraging pilot studies and clinical trials were reported, so far immunotherapeutic approaches were obviously hampered by the lack of defined target antigens (Ehtesham et al, 2004). Therefore, dendritic cells (DCs) pulsed with crude tumour cell homogenates or undefined peptide mixtures eluted from tumour cells were frequently used to augment glioma-reactive CTLs (Rutkowski et al, 2004;Yu et al, 2001Yu et al, , 2004Yamanaka et al, 2003Yamanaka et al, , 2005.…”

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

“…In comparative clinical trials of gene therapy for malignant brain tumors, first-generation adenoviral vectors are significantly more effective than retroviral vectors, utilizing the conditional cytotoxic gene HSV 1 -TK and ganciclovir (Immonen et al, 2004). Numerous clinical trails for glioblastoma multiforme using first generation adenoviral vectors have been performed or are ongoing (Sandmair et al, 2000;Trask et al, 2000;Eck et al, 2001;Ehtesham et al, 2004;Immonen et al, 2004), including an ongoing Phase III multicenter trial in Europe and Israel (see http://www.virtualtrials.com/news3.cfm?item = 3785) by Ark Therapeutics, Inc.…”

Clinical trials of gene therapy, virotherapy, and immunotherapy for malignant gliomas

“…Treatment approaches aimed at enhancing the patient's antitumor immune response, which have already demonstrated promising results in prelinical investigations and in pilot studies in humans, 57 could represent an effective adjuvant to conventional therapy to eradicate brain tumors. On the other hand, immunotherapy for malignant gliomas is a hard task, since these neoplasms are characterized by potent immunosuppressive properties, probably mediated by chemokines produced by the tumor, such as transforming growth factor beta and IL-10, that depress host antitumor immune response.…”

“…On the other hand, immunotherapy for malignant gliomas is a hard task, since these neoplasms are characterized by potent immunosuppressive properties, probably mediated by chemokines produced by the tumor, such as transforming growth factor beta and IL-10, that depress host antitumor immune response. 57 In fact, patients with malignant gliomas typically show lymphopenia, depressed T-cell responsiveness and antibody production and impaired antigen-presenting cell (APC) function. Moreover, glioma cells downregulate expression of major histocompatibility complex molecules, while overexpressing Fas ligand on their surface, thus inhibiting antitumor cytotoxic T lymphocyte (CTL) activity.…”