Info

Closed 1997

Not known

Not given

Not known

None

Unknown

Unknown

Unknown

Unknown

None

and 12-mo survival rates were 50 vs 55% in the gene therapy and control groups, respectively. These differences were not statistically significant.

There has been an anecdotal case report of a patient whose malignant glioma responded favorably to treatment with VPC-retrovirus-TK/ganciclovir gene therapy for at least 3 yr. Death from an unrelated cause led to postmortem analysis of the brain. This failed to show evidence of tumor, leading to the assertion of a cure. In spite of this, the results of the phase III trial indicate that significant advances and refinements will be needed to show that this technology can work.

The second vector studied in clinical trials is based on adenovirus. Between 1996 and 1998, 13 patients with recurrent glioblastoma multiforme were treated with a single intratumoral injection in escalating doses that ranged from 2 x 109 up to 2 x 1012 vector particles (VPs) of a replication-defective adenoviral vector bearing HSV-TK, followed eventually by ganciclovir treatment. Doses of 2 x 1011 VPs or less were tolerated, but patients treated with 2 x 1012 VPs exhibited CNS toxicity, causing confusion, hyponatremia, and seizures. One patient was reported alive and stable 29.2 mo after treatment, and two patients survived 25 mo before succumbing to tumor progression. Neu-ropathologic examination of postmortem tissue confirmed intratumoral foci of coagulative necrosis with variable infiltration of residual tumor with macrophages and lymphocytes (74).

Retroviruses were compared with adenoviruses in a phase I/II trial in Finland between 1998 and 1999, in which 21 patients with primary or recurrent glioblastoma multiforme were randomly divided into three groups (75). At the time of surgical resection, the two experimental groups were treated with VPCs producing retroviruses expressing HSV-TK or adenoviruses expressing HSV-TK; the control group received either adenovirus or VPCs expressing E. coli P-galactosidase, a marker gene. After subsequent GCV treatment, mean survival times were 7.4 (retrovirus), 8.3 (control), and 15.0 mo (adenovirus). Although the differences between mean survival times of the retrovirus and control groups were not statistically significant, the differences between the adeno-virus group and the other two groups were significant (p < 0.012). No adverse effects occurred. The explanations offered for the greater efficacy of the aden-ovirus group were greater titer, a benefit from the inflammatory reaction to ade-novirus, and the ability of adenovirus to infect nondividing cells. It is important to remember that the latter two features have also been raised also as safety concerns for adenovirus.

The third virus to undergo clinical trials in brain tumor therapy is HSV-1. Recently, two groups performed phase I dose-escalation safety trials of replication-selective HSVs in the treatment of malignant brain tumors. A Scottish group evaluated the y34.5 mutant 1716 in nine patients with brain tumors between 1997 and 1999 (76), and a U.S. group evaluated the double y34.5 and ribonucleotide reductase mutant G207 in 21 patients with brain tumors (77). Patients in the Scottish trial received lower doses of virus (between 103 and 105 PFU) than patients in the US trial (between 106 and 3 x 109 PFU), perhaps because of safety concerns.

In the 1716 trial, three patients each received 103, 104, and 105 PFU of 1716 by a single intratumoral injection (76). No adverse effects, including encephalitis, were seen that could be attributed to the administration of 1716. Five patients died of tumor progression at the conclusion of the 14-24 mo study. The thallium SPECT volumes were smaller in one, stable in two, larger in five, and not assessable in one patient.

In the G207 trial, 21 patients received doses ranging from 106 PFU in a single site to 3 x 109 PFU at five sites between 1998 and 1999 (77). Two patients had long-term expression of the P-galactosidase reporter gene found in G207 56 and 157 d after inoculation. No encephalitis was reported or found at autopsy. Four of the 21 patients were alive at the time the results were published. No deaths were attributable to the viral vector. Six of 21 patients had a decrease in the enhancement volume on MRI 1 mo after viral inoculation (77).

Finally, the onoclytic adenovirus 0NYX-015 was evaluated in a dose-escalating trial for patients with recurrent malignant glioma between 1999 and 2002 (New Approaches to Brain Tumor Therapy Consortium Trial Number 9701). Injections were performed in brain adjacent to tumor resected at surgery. The treatment was well tolerated by 24 enrolled patients, even at the highest injected dose of 1010 PFU.

Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook


Post a comment