Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector—producer cells followed by intravenous ganciclovir administration

Rj, Packer; Raffel, Corey; Jg, Villablanca; Jc, Tonn; Se, Burdach; Burger, K. J.; LaFond, Deborah; Jg, McComb; Ph, Cogen; Vézina, Gilbert; Lp, Kapcala

doi:10.3171/jns.2000.92.2.0249

Cited by 80 publications

(14 citation statements)

References 7 publications

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“…Median survival was less than 7 months, with 25% of patients living longer than 12 months. Pediatric brain tumor patients having ependymomas and primitive neuroectodermal tumors, in addition to malignant gliomas, have now been safely treated with retrovirus-mediated HSV-TK gene therapy [45]. Clinical trials are currently open for patients with malignant glioma in which retrovirus or recombinant adenovirus is being used to deliver the HSV-TK gene.…”

Section: Gene-directed Enzyme Prodrug ('Suicide Gene') Therapymentioning

confidence: 98%

Gene therapy for brain tumors

Bansal

Engelhard

2000

Curr Oncol Rep

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"Gene therapy" can be defined as the transfer of genetic material into a patient's cells for therapeutic purposes. To date, a diverse and creative assortment of treatment strategies utilizing gene therapy have been devised, including gene transfer for modulating the immune system, enzyme prodrug ("suicide gene") therapy, oncolytic therapy, replacement/therapeutic gene transfer, and antisense therapy. For malignant glioma, gene-directed prodrug therapy using the herpes simplex virus thymidine kinase gene was the first gene therapy attempted clinically. A variety of different strategies have now been pursued experimentally and in clinical trials. Although, to date, gene therapy for brain tumors has been found to be reasonably safe, concerns still exist regarding issues related to viral delivery, transduction efficiency, potential pathologic response of the brain, and treatment efficacy. Improved viral vectors are being sought, and potential use of gene therapy in combination with other treatments is being investigated.

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Section: Gene-directed Enzyme Prodrug ('Suicide Gene') Therapymentioning

confidence: 98%

Gene therapy for brain tumors

Bansal

Engelhard

2000

Curr Oncol Rep

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“…A phase I study has demonstrated the safety of in vivo gene transfer in children with poor-risk CNS tumours. Multiple injections of murine vector producing cells are made into the tumour cavity, followed 14 days later by therapy with ganciclovir for two weeks [69]. Although the clinical efficacy of this therapy is as yet unknown, the pre-treatment of human high-grade glioma xenografts with proteases enhances the transfer of adenovirus mediated HSV-TK1/ganciclovir gene therapy [70].…”

Section: Gene Therapy Biological and Gene Therapies Cancer Vaccines mentioning

confidence: 99%

Novel Targets for Therapy in Paediatric Oncology

Estlin¹

2002

curr drug targets immune endocr metabol disord

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Although the majority of children with cancer are now cured of their disease, a significant number either have disease resistant to current therapy, or are unable to tolerate the short and long term complications of their treatment. Therefore new therapeutic strategies which optimise existing agents by use of their clinical and molecular pharmacology are needed, along with the development of new agents. Accordingly, the agents chosen for the study need to be prioritized, and are thus selected on the basis of categories such as encouraging pre-clinical data from xenografts of paediatric tumours, novel mechanisms of action, drugs that modify or overcome cellular resistance and drugs that are active in adult studies. In this review, novel targets for chemotherapy such as topoisomerase I, angiogenesis and signal transduction will be discussed. In addition, the circumvention of methotrexate resistance by novel antifolate thymidylate synthase inhibition, and the modulation of alkylating agents by inhibition of 0(6)-alkylDNA-alkyltransferase will be discussed as strategies to overcome potentially important resistance mechanisms in paediatric oncology. Finally, recent advances in biological therapies, tumour vaccination and gene therapy will be highlighted. In the future, investigation of cancer biology, selection of new drugs, and securing of funds to support the conduct of integrated early clinical studies that maximise the pharmacological, cellular biological and molecular pathological information gained, will be the major challenges to be faced by paediatric oncologists.

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“…Most studies involve implanting VPCs into the cavity of resected tumors. After VPCs implantation, virus diffused into surrounding tissue and ganciclovir was administered; patients were evaluated for survival and toxicity [Izquierdo et al, 1996;Ram et al, 1997;Klatzmann et al, 1998;Shand et al, 1999;Packer et al, 2000;Rainov et al, 2000;Prados et al, 2003]. VPCs in small tumors produced anti-tumor effects [Izquierdo et al, 1996;Ram et al, 1997] and individual case studies showed increased immune response following treatment [Izquierdo et al, 1996;Floeth et al, 2001;Kramm et al, 2002].…”

Section: Conditional Cytotoxicitymentioning

confidence: 99%

Gene Therapy and Targeted Toxins for Glioma

Castro

Candolfi

Kroeger

et al. 2005

CGT

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The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted, this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors.

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Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector—producer cells followed by intravenous ganciclovir administration

Abstract: This Phase I study demonstrates that in vivo gene therapy in which a replication-defective retroviral vector in murine vector-producing cells is delivered by brain injections can be performed with satisfactory safety in a select group of children with localized supratentorial brain tumors.

Cited by 80 publications

References 7 publications

Gene therapy for brain tumors

Gene therapy for brain tumors

Novel Targets for Therapy in Paediatric Oncology

Gene Therapy and Targeted Toxins for Glioma

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