A Phase I Open-Label, Dose-Escalation, Multi-Institutional Trial of Injection with an E1B-Attenuated Adenovirus, ONYX-015, into the Peritumoral Region of Recurrent Malignant Gliomas, in the Adjuvant Setting

Abstract

ONYX-015 is an oncolytic virus untested as a treatment for malignant glioma. The NABTT CNS Consortium conducted a dose-escalation trial of intracerebral injections of ONYX-015. Cohorts of six patients at each dose level received doses of vector from 10(7) plaque-forming units (pfu) to 10(10) pfu into a total of 10 sites within the resected glioma cavity. Adverse events were identified on physical exams and testing of hematologic, renal, and liver functions. Efficacy data were obtained from serial MRI scans. None of the 24 patients experienced serious adverse events related to ONYX-015. The maximum tolerated dose was not reached at 10(10) pfu. The median time to progression after treatment with ONYX-015 was 46 days (range 13 to 452 + days). The median survival time was 6.2 months (range 1.3 to 28.0 + months). One patient has not progressed and 1 patient showed regression of interval-increased enhancement. With more than 19 months of follow-up, 1/6 recipients at a dose of 10(9) and 2/6 at a dose of 10(10) pfu remain alive. In 2 patients who underwent a second resection 3 months after ONYX-015 injection, a lymphocytic and plasmacytoid cell infiltrate was observed. Injection of ONYX-015 into glioma cavities is well tolerated at doses up to 10(10) pfu.

Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients

“…However, these tumor cells may be eradicated by administration of viral vectors carrying suicide genes such as thymidine kinase (TK) or cytosine deaminase (CD). 2,3 Adenoviral vectors are among the most promising gene delivery vehicles currently available because: (1) intratumoral administration of adenovirus type 5 (Ad5)-based vectors in malignant glioma patients has demonstrated excellent safety; [4][5][6][7] (2) high titer batches of Ad5 can be produced at large scale; (3) large segments of foreign DNA can be incorporated into Ad5 and (4) Ad5 does not integrate into the host genome. In a recently published randomized controlled study, Ad5-TK increased the median survival time from 38 to 62 weeks in malignant glioma patients.…”

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

“…First-generation adenoviral vectors are powerful vectors for gene transfer and gene therapy in the CNS (Bilang-Bleuel et al, 1997;Bemelmans et al, 1999;Dewey et al, 1999;Bjorklund et al, 2000;Mittoux et al, 2000;Sandmair et al, 2000;Maleniak et al, 2001;Mittoux et al, 2002;Biglari et al, 2004;Chiocca et al, 2004;Do Thi et al, 2004;Gondi et al, 2004;HurtadoLorenzo et al, 2004;Immonen et al, 2004). As a result, recent trials have shown adenoviral vectors encoding HSV1-TK to be effective in randomized clinical trials for brain glioblastoma multiforme, compared to patients treated with standard treatment.…”

“…Experimentally, they are successful in gene therapy models of many brain diseases, including Parkinson's disease (Bilang-Bleuel et al, 1997;Bjorklund et al, 2000;Do Thi et al, 2004;), Huntington's disease (Bemelmans et al, 1999;Mittoux et al, 2000;Mittoux et al, 2002), brain tumors (Dewey et al, 1999;Sandmair et al, 2000;Maleniak et al, 2001;Biglari et al, 2004;Chiocca et al, 2004;Gondi et al, 2004;Immonen et al, 2004) and various pain syndromes (Cope et al, 2006). 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).…”

Gene Therapy of Glioblastoma Multiforme - Clinical Experience on the Use of Adenoviral Vectors

“…However, in this trial the maximum tolerated dose was not reached. All patients showed tumour progression with a median time of 46 days and a median survival time of 6.2 months (Chiocca et al, 2004). One patient with anaplastic astrocytoma had stable disease and two patients who underwent a second resection had lymphocytic and plasmacytoid cell infiltration at the site of injection.…”