Brain Tumor Gene Therapy Clinical Trials

Three viruses have been studied in completed brain tumor gene therapy clinical trials—retrovirus, adenovirus, and herpesvirus; the former two were genetically modified to express HSV-TK with concurrent GCV administration , and the latter two were used as a replication-conditional oncolytic agent in the absence of GCV administration (see Table 2A on p. 287 and 2B on pp. 288-289).

The first study of brain tumor gene therapy in human patients occurred when a retroviral vector carrying HSV-TK was inoculated into recurrent brain tumors in 1992, just 2 yr after the first human gene therapy of any kind was undertaken in a 4-yr-old girl with adenosine deaminase deficiency. The goals of the study were to assess safety, examine the survival of murine VPCs in human tumors, determine the degree of in vivo gene transfer to tumor cells, look for evidence of escape of the genetic vector outside the area of treatment, determine whether intratumoral transplantation of xenogenic cells into human brain tumors elicits an immune response, and detect evidence of local antitumor activity in human tumors. The study involved 15 patients with malignant brain tumors who had failed standard therapy (68). Patients received stereotactic injections of HSV-TK VPCs throughout the MRI gadolinium-enhancing portion of their tumors. Eight patients showed a greater than 25% reduction in gadolinium enhancement on MRI immediately after GCV administration, and four patients showed sustained reduction, but not cure, 4-18 mo after treatment. Quantitative polymerase chain reaction (PCR) and in situ hybridization performed on tumors resected 7 d after producer cell implantation revealed a low in vivo transduction efficiency (<0.17%), suggesting that the bystander effect was vital to any observed therapeutic response (68).

These results led to a phase I/II dose-escalating open study running from 1995 to 1996 in France involving 12 patients with recurrent glioblastoma multiforme. The surface of tumor volume remaining had to be 75 cm2 or less. VPCs were injected at a total dose proportional to tumor surface volume along needle tracks spaced 1 cm apart to a maximum depth of 1.5 cm, followed eventually by GCV treatment. No treatment-related adverse effects occurred. Overall median survival was 206 d, with 25% of the patients surviving longer than 12 mo. One patient was free of recurrence at 2.8 yr after treatment (69).

A similar phase I study was performed in 12 children between ages 2 and 15 treated between 1995 and 1997. These children had recurrent tumors and received 10 mL of VPCs at multiple sites at concentrations of 107-108 cells/mL, followed eventually by GCV treatment. Disease progression occurred at a median time of 3 mo after treatment, with the three longest times until progression being 5, 10, and 24 mo. No adverse effects were documented (70).

A similar international, multicenter, open-label uncontrolled phase II study occurred between 1997 and 1998. In this study, 48 patients with recurrent GBM underwent optimal tumor resection, at which time a VPC suspension was administered through 0.2-mL (VPC density 108 cells/mL) injections spaced 0.5-1 cm apart each time to a depth of 1-2 cm, followed eventually by GCV administration. The VPCs were modified compared with the previous study, with additional unnecessary DNA sequences in the retroviral construct deleted to produce higher retroviral titers and improved transduction rates. The median survival time was 8.6 mo, and the 12-mo survival rate was 27%. Tumor recurrence was absent on MRI in seven patients for at least 6 mo, and for at least 12 mo in two patients. One patient remained recurrence free at 24 mo ( ).

To assess further the safety of VPC injections, rate of tumor cell transduction, amplitude of immune response, and degree of antitumor effect, a recent study combined gene marking with a therapeutic trial. In this study, five patients underwent two trials of intratumoral VPC implantation (first, three aliquots of 106 VPCs in columns; second, 5 ds later), separated by an intermediate harvest of implanted tumor for neuropathological study, and followed eventually by GCV treatment. Four patients tolerated the procedure well but experienced

Table 2A

Summary of Clinical Trials in Brain Tumor Gene Therapy: 21 Open Trialsa

Table 2A

Summary of Clinical Trials in Brain Tumor Gene Therapy: 21 Open Trialsa

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