Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma

Everson, Richard; Graner, Michael W.; Gromeier, Matthias; Vredenburgh, James J.; Desjardins, Annick; Reardon, David A.; Friedman, Henry S.; Bigner, Darell D.; Sampson, John H.

doi:10.1586/14737140.8.5.717

Cited by 11 publications

(7 citation statements)

References 136 publications

(128 reference statements)

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“…In our studies, we observed that CED of bevacizumab caused enlarged, dilated blood vessels (data not shown), which also may enable more chemotherapeutic agents to enter into the tumor in a manner other than normalization. Bevacizumab may have a direct therapeutic effect on tumor vasculature; we show here, and others have reported, that bevacizumab can be effective as a monotherapy, 4,9,31 which suggests that the effects of bevacizumab can be independent of chemotherapy. However, because combination therapy with bevacizumab is more effective than monotherapy, the normalization of vessels is important but only partly responsible for the effects of bevacizumab therapy.…”

Section: Fig 2 Ced Of Bevacizumab Enhanced Survival A: Animals Beasupporting

confidence: 74%

Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals

Wang¹,

Sivakumar²,

Torres³

et al. 2015

FOC

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OBJECT Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution. METHODS Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels. RESULTS The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD compared with that of IV-treated tissues. In additional studies, the infiltration of macrophages and dendritic cells into CED-treated animals were increased compared with those in IV-treated animals, suggesting a highly active inflammatory response taking place in CED-treated mice. CONCLUSIONS The administration of bevacizumab via CED increases survival over that of treatment with IV bevacizumab. Thus, CED of bevacizumab alone or in combination with chemotherapy can be an effective protocol for treating gliomas.

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Section: Fig 2 Ced Of Bevacizumab Enhanced Survival A: Animals Beasupporting

confidence: 74%

Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals

Wang¹,

Sivakumar²,

Torres³

et al. 2015

FOC

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“…Therefore, much of today's preclinical research is focused on alternate approaches, such as more selective therapies, which specifically target intracellular signaling pathways or surface molecules (44, 84), antiangiogenesis strategies (46) and especially immunotherapy. Acknowledging that different aspects of immunotherapy for malignant gliomas have been extensively reviewed in the last couple of years (149, 97, 66, 144, 94, 96, 28, 41, 27, 116, 2, 3, 133, 102, 17, 140, 38, 79, 141), the aim of the present paper is to present our own translational research program efforts as a disease‐specific paradigm for active specific immunotherapy, rather than contributing one more encyclopedic review of dendritic cell (DC) therapy overall.…”

Section: Introductionmentioning

confidence: 99%

Dendritic Cell Therapy of High‐Grade Gliomas

Gool¹,

Maes²,

Ardon³

et al. 2009

Brain Pathology

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The prognosis of patients with malignant glioma is poor in spite of multimodal treatment approaches consisting of neurosurgery, radiochemotherapy and maintenance chemotherapy. Among innovative treatment strategies like targeted therapy, antiangiogenesis and gene therapy approaches, immunotherapy emerges as a meaningful and feasible treatment approach for inducing long-term survival in at least a subpopulation of these patients. Setting up immunotherapy for an inherent immunosuppressive tumor located in an immune-privileged environment requires integration of a lot of scientific input and knowledge of both tumor immunology and neuro-oncology. The field of immunotherapy is moving into the direction of active specific immunotherapy using autologous dendritic cells (DCs) as vehicle for immunization. In the translational research program of the authors, the whole cascade from bench to bed to bench of active specific immunotherapy for malignant glioma is covered, including proof of principle experiments to demonstrate immunogenicity of patient-derived mature DCs loaded with autologous tumor lysate, preclinical in vivo experiments in a murine orthotopic glioma model, early phase I/II clinical trials for relapsing patients, a phase II trial for patients with newly diagnosed glioblastoma (GBM) for whom immunotherapy is integrated in the current multimodal treatment, and laboratory analyses of patient samples. The strategies and results of this program are discussed in the light of the internationally available scientific literature in this fast-moving field of basic science and translational clinical research.

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“…Also it can significantly improve immunity [40], [41], [42], [43], [44]. We utilized the strategy of co-expressing tumor-specific antigen genes and adjuvant genes using a bicistronic plasmid and subsequently evaluated the protective effects induced by these candidate vectors.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Antitumor Immunity Using a DNA-Based Replicon Vaccine Derived from Semliki Forest Virus

Zhang¹,

Wang

Xiao

et al. 2014

PLoS ONE

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A DNA-based replicon vaccine derived from Semliki Forest virus, PSVK-shFcG-GM/B7.1 ( Fig. 1a ) was designed for tumor immunotherapy as previously constructed. The expression of the fusion tumor antigen (survivin and hCGβ-CTP37) and adjuvant molecular protein (Granulocyte-Macrophage Colony-Stimulating Factor/ GM-CSF/B7.1) genes was confirmed by Immunofluorescence assay in vitro, and immunohistochemistry assay in vivo. In this paper, the immunological effect of this vaccine was determined using immunological assays as well as animal models. The results showed that this DNA vaccine induced both humoral and cellular immune responses in C57BL/6 mice after immunization, as evaluated by the ratio of CD4+/CD8+ cells and the release of IFN-γ. Furthermore, the vaccination of C57BL/6 mice with PSVK-shFcG-GM/B7.1 significantly delayed the in vivo growth of tumors in animal models (survivin+ and hCGβ+ murine melanoma, B16) when compared to vaccination with the empty vector or the other control constructs ( Fig. 1b ). These data indicate that this type of replicative DNA vaccine could be developed as a promising approach for tumor immunotherapy. Meanwhile, these results provide a basis for further study in vaccine pharmacodynamics and pharmacology, and lay a solid foundation for clinical application.

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Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma

Cited by 11 publications

References 136 publications

Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals

Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals

Dendritic Cell Therapy of High‐Grade Gliomas

Enhancement of Antitumor Immunity Using a DNA-Based Replicon Vaccine Derived from Semliki Forest Virus

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