Intravenous recombinant interferon beta in patients with recurrent malignant gliomas: a phase I/II study.

Yung, W. K. Alfred; Prados, Michael D.; Levin, Victor A.; Fetell, Michael R.; Bennett, J M; Mahaley, M. S.; Salcman, Michael; Etcubanas, Erlinda

doi:10.1200/jco.1991.9.11.1945

Cited by 87 publications

(32 citation statements)

References 12 publications

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“…IFN-h is a particularly good choice to show the proof of principle of this approach because phase I clinical trials of recombinant human IFN-h have shown that although responses do occur, systemic delivery of high doses of IFN-h is associated with toxicity and a narrow therapeutic index that limits the overall efficacy (48)(49)(50)(51)(52). Because IFN-h functions physiologically as a paracrine factor, its antitumoral effects can be enhanced and its toxicity is reduced if it is given locally (53,54).…”

Section: Discussionmentioning

confidence: 99%

Human Bone Marrow–Derived Mesenchymal Stem Cells in the Treatment of Gliomas

et al. 2005

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The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1A, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-B (hMSC-IFN-B). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-B against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-B significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage. (Cancer Res 2005; 65(8): 3307-18)

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Section: Discussionmentioning

confidence: 99%

Human Bone Marrow–Derived Mesenchymal Stem Cells in the Treatment of Gliomas

et al. 2005

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“…radiation or other chemotherapeutic drugs (9,(31)(32)(33). IFN-ß has also been used for patients with solid tumors including malignant gliomas with only marginal benefit; a therapeutic guideline for optimal clinical efficacy has not been determined (23,34). It has been reported that the antitumor effect of IFN-ß can be improved through the combination with chemotherapy and radiation therapy (26).…”

Section: Suppression Of U-87 Cell Migration By Tmz and Ifn-ß Combinatmentioning

confidence: 99%

“…Also, several in vitro and in vivo studies (16)(17)(18)(19) have demonstrated an antiangiogenic activity attributed to IFN-ß in tumors. Chronic systemic administration of IFN-· or IFN-ß has been observed to produce regression of vascular tumors including Kaposi sarcoma (20), pulmonary hemangiomatosis (21), and hemangiomas (22); with only a marginal benefit for malignant gliomas (23). It has been reported that the combination of IFN with chemotherapy drugs increases the antitumor effects (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Potentiation of antiglioma effect with combined temozolomide and interferon-β

Park

Joe²,

Kim³

et al. 2006

Oncol Rep

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Abstract. Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity against high grade glioma. Interferon-ß (IFN-ß) is known to have antiproliferative and antiangiogenic activities. The aim of this study was to elucidate whether an antiglioma effect could be potentiated by the combination of TMZ and IFN-ß. In vitro, the combination of these drugs suppressed the proliferative and migratory activities, as well as enhance of the apoptosis and cell cycle (S phase) arrest of U-87 cells more efficiently than TMZ or IFN-ß alone. IFN-ß exerted a potent inhibitory effect on the proliferation of human umbilical vein endothelial cells (HUVEC); however, no additive or synergistic effect was observed with the addition of TMZ. To determine in vivo effect, nude mice bearing intracerebral U-87 xenograft inoculation were treated with intraperitoneal administration of PBS, TMZ (15 mg/kg for 3 days), IFN-ß (2x10 5 IU for 15 days), and a TMZ + IFN-ß combination. The combined treatment (median 62.0±8.6 days, P=0.0005) was observed to significantly increase the survival of the animals compared to treatment with PBS (median 30.0±2.5 days), TMZ (median 41.0±3.5 days) or IFN-ß (mean 36.0±2.5 days). These results suggest that antiglioma activity can be enhanced by the combination of TMZ and IFN-ß, providing the possibility for a new strategy development in the management of malignant glioma.

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“…The first biologic immunomodulatory treatment used in the management of glioblastoma was interferon (IFN). Several clinical trials of IFN either alone or in combination with cytotoxic chemotherapy have been conducted, but treatment is associated REviEW Domingo-Musibay & Galanis future science group with significant side effects related to therapy, including fatigue and flu-like symptoms, without convincing evidence of efficacy [41][42][43].…”

Section: Immunotherapeutic Approachesmentioning

confidence: 99%

What Next for Newly Diagnosed Glioblastoma?

Domingo-Musibay

Galanis

2015

Future Oncol.

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Glioblastoma is the most common primary brain tumor in adults. Despite current multimodality treatment including surgical resection and temozolomide-based chemoradiotherapy, median survival is only 14-16 months. Characterization of molecular alterations in glioblastoma has identified prognostic subgroups and therapeutic opportunities for clinical trials across glioblastoma subsets. Following a number of negative Phase III trials testing temozolomide dose intensification and angiogenesis inhibition, recent interim analysis data indicate survival prolongation with use of a device (Optune™) delivering alternating electrical field therapy in newly diagnosed glioblastoma patients. In this review, we present an overview of the data supporting the current standard of care and discuss novel experimental therapies in early and late phase clinical testing including devices, small molecule drugs, angiogenesis inhibitors, oncolytic virotherapy and immunotherapy. KEYWORDSGlioblastoma (grade IV astrocytoma) is the most common primary brain tumor in adults. Median survival is 14-16 months after diagnosis, and survival following progression is on average only 6-8 months [1]. The WHO classification of grade IV astrocytomas also includes gliosarcoma, which shares clinical and genetic similarities with glioblastoma, and giant cell glioblastoma, which represents a distinct subset with comparatively better prognosis [2][3][4]. A new version of WHO c lassification incorporating molecular markers is expected to be released in spring 2016.In the past decade, there have been important gains in our understanding of genetic alterations associated with gliomagenesis, although this knowledge to date has not been translated into significant survival improvements. Better understanding of key pathways driving tumor growth and development and the role of the tumor microenvironment extends the promise of further improvements in therapy. Surgery, radiation and chemotherapy have established roles with some room for refinement, but new devices, small molecule cell cycle inhibitors, biologic and immune-based therapies have started yielding promising results in Phase II and early readings of Phase III trials and create optimism for future changes in the treatment landscape and standard of care. Standard-of-care therapyThe standard backbone in the treatment of newly diagnosed glioblastoma is surgical resection, when feasible, followed by radiation therapy (RT) administered concurrently with oral temozolomide (TMZ), followed by six cycles of adjuvant TMZ therapy. RT for glioblastoma has formed the basis of postoperative therapy for decades [5]; developments in radiation delivery techniques have led to the current standard of involved field RT at a dose of 60 Gy delivered in 30 fractions. Increasing RT dose up to 90 Gy has been studied, and it provides no additional benefit regardless of the For reprint orders, please contact: reprints@futuremedicine.com

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Intravenous recombinant interferon beta in patients with recurrent malignant gliomas: a phase I/II study.

Cited by 87 publications

References 12 publications

Human Bone Marrow–Derived Mesenchymal Stem Cells in the Treatment of Gliomas

Human Bone Marrow–Derived Mesenchymal Stem Cells in the Treatment of Gliomas

Potentiation of antiglioma effect with combined temozolomide and interferon-β

What Next for Newly Diagnosed Glioblastoma?

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