WASHINGTON -- Two biotechnology products were given thego-ahead for human testing by the Recombinant DNA AdvisoryCommittee (RAC) of the National Institutes of Health (NIH) hereon Thursday. Cell Genesys Inc.'s anti-HIV modified T cellproduct was approved "with conditions" to enter Phase I/IItrials, and Viagene Inc.'s gene therapy product for a potentiallyfatal form of childhood cancer was cleared to begin Phase Isafety trials.

Cell Genesys' trial -- the Foster City, Calif., company's first inhumans -- will be run by investigators at the National Instituteof Allergy and Infectious Diseases (NIAID) under a CooperativeResearch and Development Agreement (CRADA). RAC said thetrial sponsors must submit more laboratory data from in vitrostudies now under way and make minor changes in theprotocol before the Phase I/II trial can begin.

The trial will test the safety of T cells modified using aretroviral vector that encodes for a novel receptor comprised ofthe CD4 protein linked to an intracellular zeta (a signalingprotein) chain. The modified T cells could theoretically behaveas pre-targeted killer cells that attack and destroy HIV-infected cells due to their specificity for glycoprotein 120(gp120), a substance on the surface of HIV-infected cells.

Re-engineering CD8 Cells

"What we're doing is re-engineering CD8 cells to be specific,and that's absolutely unique," Daniel Hoth, senior vice presidentat Cell Genesys and former director of NIAID's AIDS Division,told BioWorld. "We're adding a property to a cell, making itrecognize and kill another cell."

The trial will be conducted in pairs of identical twins in whichone of the twins is infected with AIDS and one is not.Approximately 140 such pairs have registered so far withNIAID as potential participants in experimental drug trials. Tcells will be harvested from the healthy twin, transduced withCell Genesys' retroviral vector, expanded ex vivo and theninfused into the HIV-infected twin. Normal problems ofimmunological compatibility will be avoided because identicaltwins are syngeneic (essentially chromosomal clones of oneanother).

The identical twin HIV trial, planned to enroll 40 patients, is a"proof-of-concept" study, according to Hoth. If the modified Tcells prove safe, the vector will be tested in much larger HIVpatient populations. Robert Walker, senior investigator ofNIAID's intramural AIDS program, and Clifford Lane, clinicaldirector of NIAID, will serve as principal investigators andsponsors of the trial.

Unmasking Cancer Cells

Viagene's product is a retroviral vector that delivers the genefor gamma interferon to dividing cells, such as cancer cells. RACgave the go-ahead Thursday for a trial testing the therapy inchildren suffering from neuroblastoma, a malignant tumorformed from embryonic ganglion cells. The ex vivo genetherapy is currently in another RAC-approved trial formelanoma. In addition, Viagene of San Diego is currentlyconducting three RAC-approved Phase I safety trials with agene transfer product for the treatment of HIV infection.

In the neuroblastoma trial, researchers will take a biopsy ofthe patient's tumor, transduce the cells with a retroviral vectorfor the gamma interferon gene, expand the modified cells,irradiate them and inject them into the patient. The end resultwill be cancer cells modified to produce gamma interferon.

Intracellularly produced gamma interferon is known toincrease production of major histocompatibility complex (MHC)molecules, crucial elements of the immune system. MHC alertsimmune cells to the presence of foreign substances in the body,but cancer cells stop producing normal amounts of MHC andthus are able to wreak havoc under a sort of non-MHC cloakingdevice. Viagene (NASDAQ:VIGN) believes its product has thepotential to unmask cancer cells by causing them to produceMHC in quantities that will attract lethal attention from theimmune system.

Neuroblastoma affects about 500 children in the U.S. each year.Despite the small numbers, Viagene's president and chiefexecutive officer, Robert Abbott, told BioWorld that patientaccrual would not be a problem because treatment of childhoodcancer is highly regionalized, with a small number of expertsand centers nationwide.

Abbott explained that the company's strategy is to test itsproduct in various types of cancer and select the optimalindication for pivotal studies. He added that the company wasnot "market-driven" in its selection of indications.

"Because this is a new technology with a lot of uncertaintysurrounding it, we are focusing on those diseases in which theproduct is most likely to work, almost without regard tomarkets," Abbott told BioWorld. However, if the product gainsapproval, even for a small disease indication, the companywould work to expand its indications.

Robert Seeger, professor of pediatrics at Children's Hospital inLos Angeles, and Joseph Rosenblatt, director of gene therapy atthe University of California, Los Angeles, are the principalinvestigators and sponsors of the investigational new drug(IND) application for the study of Viagene's vector.

-- Lisa Piercey Washington Editor

(c) 1997 American Health Consultants. All rights reserved.