Immunodeficiency is HIV's middle name _ humanimmunodeficiency virus. Ditto, AIDS _ acquired immune deficiencysyndrome.
As the degrees on a clinical thermometer measure fever, CD4 countson T cells gauge the severity of immune deficiency in HIV-infectedindividuals. T lymphocytes that display these CD4 antigens on theirsurface are a prime target of attack by the AIDS virus.
So it came as a surprise that five out of six HIV-infected patients withlow CD4 counts, ranging from 200 to 500 per cubic millimeter,(1,000 being typical of healthy people), could still scare up enoughkiller T cells (cytotoxic T lymphocytes _ CTL) in their crippledimmune systems to reject their own replacement killer T cellsreturned to them by gene therapy technology.
Nature Medicine, in its February issue, reports this unexpectedtherapeutic let-down under the title: "T-cell mediated rejection ofgene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients." The article's principal authors are immunologistsPhilip Greenberg, of the University of Washington, Seattle, andStanley Riddell at the associated Fred Hutchinson Cancer ResearchCenter.
Their custom-made gene-transfer package, Riddell told BioWorldToday, "consisted of a retroviral vector into which we inserted adual-function fusion gene. One part, a hygromycinphosphotransferase gene, allows you to select the CTL cells you areexpanding in a positive way. The other is a herpes simplex virusthymidine kinase. This renders cells susceptible to acyclovir, so itssuicide gene allows you to kill them, if you want to."
He explained: "Whenever you're doing gene therapy, or putting insomething that's been genetically altered, there is always thepossibility that something will go wrong. In our experiment, becausethey are T cells that have a specific function, they could in fact causeinflammation in the patient's body, if there was a lot of virus in avital organ, for example. So this study is really designed to look at asafety measure for gene therapy."
These retroviral vector constructs are the work of Stephen Lupton, aco-author of the paper, who directs gene expression at TargetedGenetics Corp., in Seattle
Single clones of killer T cells removed from each subject wereproliferated in culture. These CTLs were programmed by specificantigens to counterattack HIV's infective nose cone, its gag protein,by killing virus-infected cells in the body.
The educated and expanded CTLs, selected and protected by thevector-transferred fusion gene, were then returned to the patient foradoptive immunotherapy.
"We're the only group," Riddell said, "that has transferred T cellclones into people. Largely, that's because it's difficult to grow ahuman antigen-specific T cell from a single cell to several billion. Wesolved that problem."
Five of the six patients generated killer T cell responses aimed pointblank at the expanded new population of CTLs, and so wiped themout. One explanation for the sixth person's non-response, Riddellsuggested, "is that he had a very high level of HIV, so perhaps ismore immune deficient.
"What this has shown us," he observed, "is that there's a problem forthe field of gene therapy, not for the field of immunotherapy."
"One unexpected insight from these studies," the paper observed,"was the ability of HIV-infected patients to induce strong primary Tcell immune responses to foreign antigens expressed by transferredautologous CTLs. This may have potential implications for the designof immunization strategies to induce or augment immune responsesto opportunistic pathogens." AIDS patients, of course, are the primevictims of such random-hit infective microbes.
The paper's authors concluded, "The rejection of geneticallymodified cells by these immunocompromised hosts suggests thatstrategies to render gene-modified cells less susceptible to hostimmune surveillance will be required for successful gene therapy ofsuch hosts."
Promises, Promises: Dividing Up The Blame
Commenting in Nature Medicine on the Seattle experience, ScottKoenig, of MedImmune Inc., Gaithersburg, Md., warned: "Thegeneration of a primary CTL response in almost all of these HIV-infected patients does not bode well for successful maintenance ofgenetically altered and functionally active cells in fully immunecompetent hosts."
Molecular geneticist Theodore Friedmann, of the University ofCalifornia at San Diego, applied a broader brush: "Human genetherapy _ an immature genie, but certainly out of the bottle," is thetitle of his commentary in the same Nature Medicine.
Citing "more than 100 peer-reviewed studies of human genetherapy," Friedmann noted that each reported "some degree ofsuccessful [gene] transfer . . . but failure to demonstrate clinicalbenefit to treated patients."
"These apparently `negative' results," he observed, "have come assomething of a shock to some because they were in such sharpcontrast to the soaring expectations generated by early scientific andlay publicity . . . ."
Friedmann's recipe for reform: "Perhaps in the absence of therapeuticefficacy, investigators might be encouraged to present their resultsmore often as `gene transfer' studies rather than `gene therapy'studies and to downplay therapeutic interpretation until clinicalefficacy is really proven."
They Said It Would Be Easy
"Unfortunately," he commented, "explicitly or implicitly, we all _the scientists, influential major medical and research institutionsincluding the National Institutes of Health, the biotechnologyindustry, disease-based medical foundations, the scientific press andthe lay press and media _ said it would be relatively easy. We allconveyed advances _ sometimes in an unrealistically rosy way _ toa public desperate for good news about disease . . . ."
On this point, Friedmann observed, "What has frequently beenoverlooked in the mad scramble toward clinical studies, and in therecent disillusionment with clinical reports, is the astounding fact thatthe concept itself . . . has become a generally accepted driving forcein modern medicine." Moreover, "Huge commercial gene therapyenterprises, valued at many hundreds of millions of dollars, haveemerged." In this he sees "a likely sign that commercially usefultherapeutic materials will inevitably come and be applied to a largenumber of common diseases.
"Some of the many major international biotechnology andpharmaceutical corporations [that] have made enormous investmentsin human gene therapy will assuredly conclude that it is precisely theneed for improved gene transfer technology and more thoroughlycharacterized disease mechanisms that represent such attractive andpotentially lucrative areas for investment opportunities."
In concluding his lengthy down-side/up-side critique, Friedmannwrote: "Human gene therapy has not yet come of age, but there canbe no justification for doubting its eventual success, as an adjunct totraditional therapies or as a definitive therapy on its own." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.