Interstitial Infusion of Glioma-Targeted Recombinant Immunotoxin 8H9scFv-PE38

Luther, Neal; Cheung, Nai Kong V.; Souliopoulos, Eleni P.; Karempelas, Ioannis; Bassiri, Daniel; Edgar, Mark A.; Guo, Hong-Fen; Pastan, Ira; Gutin, Philip H.; Souweidane, Mark M.

doi:10.1158/1535-7163.mct-09-0996

Cited by 29 publications

(20 citation statements)

References 48 publications

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“…First attempts to use 4IgB7H3 as a therapeutic target have been made recently with an antibody against 4IgB7H3 used to track neuroblastoma cells without intending to block 4IgB7H3 function itself (39) and a pseudomonas immunotoxin-coupled anti-B7H3 antibody to track glioblastoma xenograft tumors (40). Further experiments are needed to evaluate 4IgB7H3 as a target in the treatment of 4IgB7H3-expressing tumors.…”

Section: Discussionmentioning

confidence: 99%

Costimulatory Protein 4IgB7H3 Drives the Malignant Phenotype of Glioblastoma by Mediating Immune Escape and Invasiveness

Lemke

Pfenning

Sahm

et al. 2012

Clinical Cancer Research

120

101

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Purpose: Recent work points out a role of B7H3, a member of the B7-family of costimulatory proteins, in conveying immunosuppression and enforced invasiveness in a variety of tumor entities. Glioblastoma is armed with effective immunosuppressive properties resulting in an impaired recognition and ineffective attack of tumor cells by the immune system. In addition, extensive and diffuse invasion of tumor cells into the surrounding brain tissue limits the efficacy of local therapies. Here, 4IgB7H3 is assessed as diagnostic and therapeutic target for glioblastoma.Experimental Design: To characterize B7H3 in glioblastoma, we conduct analyses not only in glioma cell lines and glioma-initiating cells but also in human glioma tissue specimens.Results: B7H3 expression by tumor and endothelial cells correlates with the grade of malignancy in gliomas and with poor survival. Both soluble 4IgB7H3 in the supernatant of glioma cells and cell-bound 4IgB7H3 are functional and suppress natural killer cell-mediated tumor cell lysis. Gene silencing showed that membrane and soluble 4IgB7H3 convey a proinvasive phenotype in glioma cells and glioma-initiating cells in vitro. These proinvasive and immunosuppressive properties were confirmed in vivo by xenografted 4IgB7H3 gene silenced glioma-initiating cells, which invaded significantly less into the surrounding brain tissue in an orthotopic model and by subcutaneously injected LN-229 cells, which were more susceptible to natural killer cell-mediated cytotoxicity than unsilenced control cells.Conclusions: Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Costimulatory Protein 4IgB7H3 Drives the Malignant Phenotype of Glioblastoma by Mediating Immune Escape and Invasiveness

Lemke

Pfenning

Sahm

et al. 2012

Clinical Cancer Research

120

101

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“…When conjugated to cobra venom factor, it induces efficient complement-mediated tumor lysis (40). In its single chain Fv (scFv) format, it targets a potent immunotoxin to sarcoma and glioma in preclinical models (41,42). As a chimeric antigen receptor, it redirects natural killer cells to kill B7-H3(ϩ)-positive tumor cells (43).…”

mentioning

confidence: 99%

Humanized Affinity-matured Monoclonal Antibody 8H9 Has Potent Antitumor Activity and Binds to FG Loop of Tumor Antigen B7-H3

Ahmed

Cheng

Zhao

et al. 2015

Journal of Biological Chemistry

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Background: B7-H3 is an immune inhibitory ligand and an antigen on many solid tumors. Results: Antibody 8H9 was humanized and affinity-matured, and its epitope was mapped to the FG loop of B7-H3. Conclusion: hu8H9 antibodies had potent antitumor activity and may modulate immune inhibitory properties of B7-H3. Significance: Antibodies were developed to target solid tumors and affect immune checkpoint blockade.

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“…The investigators tested the 8H9scFv-PE38 recombinant pseudomonas immunotoxin in a preclinical model for malignant glioma. For rats harboring intracranial U87 xenografts, an infusion of 8H9scFv-PE38 increased the mean survival (60). Tumors also showed a volumetric response to an infusion of 8H9scFv-PE38 by MRI.…”

Section: New Targeted Therapiesmentioning

confidence: 96%

Glioblastoma multiforme: Molecular characterization and current treatment strategy (Review)

Zhang

Cao

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Glioblastoma multiforme (GBM) is the most common and lethal malignant primary brain tumor. It is classified by the World Health Organization (WHO) in the group of diffusely infiltrating astrocytomas, representing up to 50% of all primary brain gliomas, and carries the poorest prognosis. Aberrant genetic events and signaling pathways have clearly demonstrated that GBM is highly anaplastic and a morphologically highly heterogeneous tumor. Understanding the genetic alterations, specific molecular biomarkers and proliferative pathways may promote therapeutic development for the management of GBM. Age, Karnofsky performance score, histology, position and the extent of tumor resection have been identified as potential prognostic factors for patients with GBM. In this study, we review the molecular characterization of tumor cells, the current standard of care for patients diagnosed with GBM, including gross or near-total resection of the tumor, followed by radiotherapy, stereotactic brachytherapy, chemotherapy and new targeted therapies. Thus, we conclude that multimodal approaches for the treatment of patients with GBM may significantly improve their prognoses. IntroductionGlioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor in humans, representing up to 50% of all primary brain gliomas, and the prognosis of patients with GBM remains poor (1,2). A grading scheme that has been proposed by the World Health Organization (WHO) distinguishes four different grades of gliomas. One of these, GBM WHO IV with predominant astrocytic differentiation, accounts for approximately 12-15% of all brain tumors and 60-75% of astrocytic tumors, and is the most malignant type (3). Approximately 51,000 primary brain tumors are diagnosed in the United States each year, 36% of which are gliomas. Half of these are GBM, with approximately 3 in 100,000 individuals newly diagnosed with GBM each year (4). The treatment difficulty is due to the exceptionally infiltrative nature of GBM and its proclivity to integrate into normal brain tissue (5). Fortunately, it is worth noting that, with the notable recent advances in therapy, an increasing number of GBM patients are surviving for 36 months or longer, so that they are referred to as long-term survivors (LTS, ≥36 months) (6). To date, the management of patients with GBM continues to harbor significant challenges, and comprehensive genetic screens of tumor tissues and signaling pathways have been explored to develop molecular-based targeted therapies (7). Molecular characterizationAlthough numerous genetic alterations have been described in GBM (8,9), such markers have proven to be of marginal utility in predicting outcome or guiding decisions regarding disease management. In general, the molecular characterization of GBM should provide a better understanding of the genomic landscape of GBMs and more efficacious means for rapid, high-throughput analyses of tumor cells and tissues.Despite common clinical presentations and histology, it has been clearly demon...

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Interstitial Infusion of Glioma-Targeted Recombinant Immunotoxin 8H9scFv-PE38

Cited by 29 publications

References 48 publications

Costimulatory Protein 4IgB7H3 Drives the Malignant Phenotype of Glioblastoma by Mediating Immune Escape and Invasiveness

Costimulatory Protein 4IgB7H3 Drives the Malignant Phenotype of Glioblastoma by Mediating Immune Escape and Invasiveness

Humanized Affinity-matured Monoclonal Antibody 8H9 Has Potent Antitumor Activity and Binds to FG Loop of Tumor Antigen B7-H3

Glioblastoma multiforme: Molecular characterization and current treatment strategy (Review)

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