When Britain, and then the U.S., mobilized to fight World War II, they had to train motley populations of civilian draftees and turn them into efficient killing machines.
A biotechnology company in California and a Harvard University teaching hospital have teamed up to fight the AIDS virus with the same strategy. It consists, as immunologist Bruce Walker told BioWorld Today, of "forcibly educating immune-system killer T cells that don't know how to recognize HIV to find and kill virus-infected T cells and macrophages."
This deprives the virus of a chance to produce new HIV particles, which would spread its DNA to other cells. Antiviral drugs used to treat AIDS can't eradicate HIV holed up inside macrophages.
T cells come in two versions: One, cytotoxic T lymphocytes, carry the CD8 receptor on their surface, which marks them as killer cells. The other, helper T cells, sports the CD4 receptor.
"The role of those cells," explained immunologist Margo Roberts, "is to help the killer cells survive and multiply. One of the main ways in which they help is by producing cytokines that maintain and enhance the T cells' cytotoxic function. Roberts is director of cell therapy at Cell Genesys, in Foster City, Calif.
She and Walker are co-senior authors of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Oct. 14, 1997. Its title: "Lysis of HIV-infected cells and inhibition of viral replication by universal receptor T cells." Walker directs the AIDS Research Center for Massachussetts General Hospital, in Charlestown, Mass., a teaching hospital of Harvard Medical School.
"Cell Genesys had already produced those universal T cells," Walker pointed out, "and we got in touch with them because we had developed an assay for determining the ability of cells to inhibit viral replication. So all the data in the paper came from our lab, but using their genetically engineered cells."
He added: "The rationale of the approach is to be able to redirect any CD8 cell that hasn't been deleted or mutilated by HIV infection to go after infected cells to become a virus-specific killer."
Having completed a Phase I trial of their anti-HIV approach, Roberts said, the two teams are now in early stages of a Phase II study at six clinical centers across the U.S. — at Harvard's Mass. General, the University of Colorado, in Boulder, the University of California, in Los Angeles and in San Francisco, plus two AIDS clinics in the San Francisco Bay Area.
Treatment Protocol Starts With Blood
Treatment begins by drawing and recycling the HIV-positive patient's blood by apheresis and collecting one percent of all T cells before returning the blood to the circulation. This initial process, Roberts observed, "takes a couple of hours, if that.
"The bulk population of packed T cells," she continued, "is a huge mixture of T cells, only a tiny fraction of which is specific for HIV."
Those hapless T cells go into culture at Cell Genesys to be genetically transformed into virus-hungry killers. "We've genetically engineered the whole population to become HIV-specific, by introducing an essentially surrogate HIV cell receptor gene into them."
Converting and expanding that mass of cells in culture before reinfusing them into the patient took three to four weeks in the Phase I trial. Going into Phase II, the genetic modification time is down to around two weeks, Roberts said.
"That controlled Phase I study," she went on, "done at the National Institutes of Health, focused on safety and cell survival. It enrolled 30 pairs of identical twins. What we were able to show," she recounted, "was that, firstly, patients tolerated a wide dose range of genetically modified T cell transfers. And secondly, those modified cells seemed to persist in the patient for months after the transfer."
The Phase II study, which began in late 1996, will enroll 80 patients, with preliminary data expected by mid-1998.
"In Phase I," Roberts pointed out, "we infused patients only with genetically modified killer T cells. Now in the ongoing Phase II trial, we are infusing them with both modified killer and helper T cells, which I think is a very critical issue."
All of these trial participants combine the experimental modified T cell treatment with the current triple-drug anti-HIV therapy. This renders more difficult the measurement of clinical efficacy.
"Luckily for us," Roberts observed, "the techniques we now have for detecting viral load are far more sensitive than they used to be. Even patients on triple-drug therapy have usually detectable, though very, very low, virus levels. So we will be able to measure them following administration of our genetically modified T cells over time.
"Triple-drug regimens," Roberts said, "aren't cheap. They can bring the level of the virus way down to manageable levels, presumably. And then you use this immune-based treatment to clean up the viral reservoirs. But it's far too early to tell if this alone can have an impact."
Chasing Down The Last HIV Particle
Whether the technique can ever mop up and wipe out the entire HIV load, down to the last viral particle, Roberts said, "is something we have no idea of. It's one of the things we'll learn in the clinic."
She went on: "Frankly, in order for this strategy to have any utility, it would be critical that the genetically modified T cells achieve what the patient's own dysfunctional T cells are unable to do, which is to target and eventually eliminate the HIV reservoirs — the infected macrophages and T cells — in the body. So that's one of the things we're looking at very carefully in the clinical trials."
Given the evidence reported in PNAS, she said, "we hope that multiple infusions of killer T cells will not be needed. The way the treatment now stands, it's a relatively cumbersome and expensive procedure, mainly because of the T cell culture that's involved.
"What we're doing now is working to develop a strategy in which the whole process will be absolutely minimal. To get to a point," she concluded, "where one could go as an outpatient to a hospital and have a blood sample taken. The gene would be introduced into your cells ex vivo, and you'd receive the modified cells back the same day." *