A year after the federal government shut down eight human gene-therapy experiments at the University of Pennsylvania, the Ivy League school has decided to give up its efforts to get most of them restarted.

The crackdown by the U.S. Food and Drug Administration followed the 1999 death of Jesse Gelsinger, an 18-year-old Arizona youth who had a fatal reaction to a gene drug being tested at Penn.

On Jan. 21, after an investigation of the campus laboratory that produced the drug, the FDA imposed a freeze on all human gene-therapy work at Penn's prestigious Institute for Human Gene Therapy, headed by James M. Wilson.

Penn officials said Friday they hoped to resume two of the eight gene trials that had been under way. The trials, they said, would be revamped and run under new supervision outside Wilson's institute.

One trial focuses on a certain type of brain tumor, the other on a particularly deadly lung cancer known as mesothelioma.

But Penn will drop its efforts to persuade the FDA to reinstate the six other institute-sponsored trials, Penn provost Robert Barchi said. Those trials involve gene therapy to treat cystic fibrosis, muscular dystrophy, breast and skin cancer, and a rare liver disease.

Wilson, who has come under severe criticism for his lax oversight of the liver-related trial that killed Gelsinger, now faces a separate FDA action that aims to strip him of his right to conduct clinical trials anywhere in the United States.

Wilson, through his lawyer, said last week he would contest the FDA's proposed action in a soon-to-be-scheduled meeting with FDA officials. He declined to comment on the specifics of the government allegations.

Barchi said the university was not backing away from gene therapy but indicated that its clinical trials in the field will no longer revolve around Wilson, once regarded as a world leader in the field.

The university now has six human gene-therapy trials under way or about to start outside Wilson's institute. They include gene-based therapies for colorectal cancer, melanoma, AIDS, peripheral arterial disease, and certain cancers of the lung, head and neck.

All are sponsored by private industry or the National Institutes of Health.

Gene therapy, which burst on the scientific scene in 1990, aroused great excitement because it held out the promise of replacing defective genes with functional ones, possible curing otherwise intractable illnesses.

Progress had been slow, however, and Gelsinger's death slowed it further. His death stirred an international controversy and cost Penn millions of dollars in a settlement with Gelsinger's estate.

Wilson, who has tenure, remains as director of the institute, but the university has significantly narrowed the scope of his program. The institute is doing only laboratory experiments and animal research related to gene therapy. Its budget has been pared from $25 million to $18 million and its staff cut from 230 to 175, Penn officials said.

Barchi said the institute still plays "a very valuable role" in basic research and preclinical studies, but he indicated it was "only a piece" of the university's much broader agenda in biomedical research.

In an initiative to be announced shortly, Penn will present plans for a major new program in the broader field of genomics, using the gene-sequencing data churned out by the international Human Genome Project to develop new diagnostic tests and new targets for therapeutic drugs to treat complex diseases such as diabetes, Barchi said.

That, he said, will be the future of medicine in the 21st century. "Gene therapy is an exciting new area, but it's an area with limited applicability," Barchi said. He pointed out that most diseases do not involve the inherited mutations in genes that gene therapy aims to correct.

Leading gene-therapy scientists on the Penn campus have expressed private concerns that the Penn administration may be making it virtually impossible for them to launch cutting-edge clinical trials.

They say the university appears to be backing off from any trial that is not sponsored by private industry or the federal government. Such a stance may have a chilling effect on innovation and choke off research on so-called orphan diseases that are suffered by so few people that neither industry nor the government is willing to finance the work, scientists say.

Barchi said the university won't rule out sponsorship of such research, but he said it will take a very hard look at such proposals.

"Clearly, we favor clinical trials sponsored by industry or the [National Institutes of Health]. They provide management with built-in [safety] monitoring."

Gelsinger's death and the subsequent investigation of Wilson's lab and other labs across the country has prompted the FDA and the National Institutes of Health to impose tough new rules aimed at protecting patient safety not only in gene-therapy trials but in all research involving human subjects.

At Penn, university officials say the school's own reforms go far beyond what the new government rules require. "I don't believe there is another research institution in the country that can match what we are doing," Barchi said.

Under the changes, he said, campus researchers have to pass a rigorous written test before being allowed to submit proposals for human trials; a thick new book of standard operating procedures for clinical trials has been developed for faculty researchers; and the system for monitoring trial safety has been greatly expanded, with high-risk trials required to be monitored by outside firms.

"We are going way beyond what the FDA and the NIH require," Barchi said

Gene Therapy for Malignant Pleural Mesothelioma

November 6, 1998

Abstract

Malignant mesothelioma (MM) is a fatal malignancy refractory to all forms of standard anticancer therapy. This article reports the results of a phase I clinical trial assessing the safety of intrapleural delivery and efficacy of intratumoral gene transfer of recombinant adenovirus (rAd) containing herpes simplex virus thymidine kinase (HSVtk) gene into the pleural space of patients with MM, followed by systematic treatment with the antiviral drug ganciclovir (GCV) for 14 days. AD.RSVtk/GCV gene therapy proved to be well tolerated, with evidence of significant gene transfer particularly at high vector doses and with elimination of preliminary biopsy. Ongoing gene therapy trials for mesothelioma at two other centers, focusing on immunostimulation and using suicide gene therapy as a tumor vaccine, are also reviewed in this article.

Address Department of Medicine, University of Pennsylvania Health System, Philadelphia, USA.
Source Hematol Oncol Clin North Am, 12(3):553-68 1998 Jun
Author Sterman DH; Kaiser LR; Albelda SM

Adenovirus-Mediated Herpes Simplex Virus Thymidine Kinase/Ganciclovir Gene Therapy in Patients with Localized Malignancy: Results of a Phase I Clinical Trial in Malignant Mesothelioma

Abstract

Malignant pleural mesothelioma is a fatal neoplasm that is unresponsive to standard modalities of cancer therapy. We conducted a phase I dose-escalation clinical trial of adenoviral (Ad)-mediated intrapleural herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) gene therapy in patients with mesothelioma as a model for treatment of a localized malignancy. The goals of this phase I trial were to assess the safety, toxicity, and maximally tolerated dose of intrapleural Ad.HSVtk, to examine patient inflammatory response to the viral vector, and to evaluate the efficiency of intratumoral gene transfer. Twenty-one previously untreated patients were enrolled in this single-arm, dose-escalation study with viral doses ranging from 1 x 10(9) plaque-forming units (pfu) to 1 x 10(12) pfu. A replication-incompetent recombinant adenoviral vector containing the HSVtk gene under control of the Rous sarcoma virus (RSV) promoter-enhancer was introduced into the pleural cavity of patients with malignant mesothelioma followed by 2 weeks of systemic therapy with GCV at a dose of 5 mg/kg twice a day. The initial 15 patients underwent thoracoscopic pleural biopsy prior to, and 3 days after, vector delivery. The last six patients underwent only the post-vector instillation biopsy.

Dose-limiting toxicity was not reached. Side effects were minimal and included fever, anemia, transient liver enzyme elevations, and bullous skin eruptions, as well as a temporary systemic inflammatory response in those receiving the highest dose. Strong intrapleural and intratumoral immune responses were generated. Using RNA PCR, in situ hybridization, immunohistochemistry, and immunoblotting, HSVtk gene transfer was documented in 11 of 20 evaluable patients in a dose-related fashion. This study demonstrates that intrapleural administration of an adenoviral vector containing the HSVtk gene is well tolerated and results in detectable gene transfer when delivered at high doses. Further development of therapeutic trials for treatment of localized malignancy using this vector is thus warranted.

Address: Division of Pulmonary and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Source: Hum Gene Ther, 9(7):1083-92 1998 May 1
Author: Sterman DH; Treat J; Litzky LA; Amin KM; Coonrod L; Molnar-Kimber K; Recio A; Knox L; Wilson JM; Albelda SM; Kaiser LR