When a patient died earlier this year during gene therapy forbrain cancer, the most frightening possibility for researcherswas that the retroviral vector had caused the new growth thathad doomed the patient.
This possibility has now been dismissed, but experimentalinfection with vectors has caused cancer in non-humanprimates. And replication-competent retroviruses haveemerged twice in clinical materials.
Monday's meeting of the advisory committee to the Center forBiologics Evaluation and Research (CBER) of the FDA on vaccinesand related biological products addressed the risks of viralvectors and how best to narrow them. From its review of thecurrent state of the art, the committee seemed comfortablewith the way industry and the FDA have been dealing with therisks.
Besides cancer, risks include side effects from normaltreatment, various pathologies from viral infection, changes inthe germ line and the possibility that a new virus might escapeinto the environment. But so far, no harm has come to humansfrom retroviral vectors.
Three basic steps to safety include designing viruses so theycannot recombine to gain the ability to reproduce, ensuringpurity, and screening.
The questions are especially compelling in the case ofretrovirus vectors, the "workhorses of the gene therapy field,"Alexander Kuta, acting branch chief of the cytokine and genetherapies branch of FDA, told the committee. Of 49 genetherapy studies for which CBER has given the green light, 41used retroviral vectors.
Two breakouts have occurred, both in June 1992. At GeneticTherapy Inc. (GTI), viruses reproduced in a manufacturing runfor clinical material. And at Viagene Inc. there was a breakoutduring development of the manufacturing process for aproposed immunotherapeutic for HIV infection, "and we had toretool," Douglas Jolly, vice president of research told BioWorld.
The GTI vector, G1Na.40, "had been designed to minimize thepotential for breakouts, with a minimum number ofhomologous sequences, as well as mutation in the start (GAG)codon," Gerard McGarrity, vice president of development at GTIof Gaithersburg, Md., told the committee.
But since then, "there are two big improvements in the newsystem," Ed Otto of GTI told the committee. The start codon isnow a stop codon, and there are still fewer homologies.
The breakout was easily detected by every method tried,McGarrity told the committee. Moreover, Kuta was optimisticthat replication competent retroviruses could be detectedreliably through the combination of biological assay andpolymerase chain reaction.
Following the presentations, the committee seemed confidentwhen it considered how to control risks rather than whether ornot retroviral vectors should be used in gene therapy.
Committee member Jerome Groopman, chief of the division ofhematology and oncology at New England Deaconess Hospital,put the patient risks in context when he alluded to "a score ofchemotherapeutic drugs which I and others use every day,mutagenic and intercalating agents." He added: "This kind oftherapy has to be put into the perspective of other patients insimilar dire circumstances."
Regarding whether more animal studies are needed to assessrisk, committee chairman Stanley Lemon, professor ofmedicine, microbiology and immunology at the University ofNorth Carolina, said, "My prediction is that in most cases wewon't see anything (adverse), but we've got to push thesystem."
As to whether studies with no direct patient benefit -- such asmarkers -- should be conducted, Groopman pointed out thatmany patients receive a psychological lift from contributing toscientific research. Lemon urged committee members to letFDA use its judgment rather than to "hem the FDA in" withstrict guidelines for acceptable studies. And with that, thecommittee took its only vote, 6-0, to allow such studies with noguidelines.
The committee also considered the safety of adenovirusvectors. Members discussed ways to mitigate the side effects --which have included inflammation of the airways during trialsamong cystic fibrosis patients -- and there was somediscussion, though no consensus, on using steroids. Lemonconcluded that he "couldn't conceive" of abandoning the CFtrials.
-- David C. Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.