September 19, 2011
The stunning success of the "Berlin patient" has spurred new life into research around immune-based therapies. These are innovative approaches to HIV treatment that involve strengthening the immune system's response to HIV infection, rather than relying on the daily use of medications to keep HIV replication at bay.
Earlier this year, biopharmaceutical firm Sangamo BioSciences, Inc., made waves (and had many people prematurely uttering the word "cure") when it offered data on a form of gene therapy that attempts to rewire an HIV-infected person's CD4+ cells so they no longer have a properly working CCR5 receptor, the primary receptor that HIV binds to before it infects the cell. Those earlier data pretty much indicated that there's a chance this thing might actually work. Further results presented here at ICAAC 2011 seem to indicate that, seriously, there's still a chance this thing might actually work.
As Ronald Mitsuyasu, M.D., of the University of California-Los Angeles, explained in his ICAAC 2011 presentation, Sangamo's gene therapy strategy (referred to as SB-728) breaks down like this:
The end result, Mitsuyasu said, is that about 25% of the cryopreserved CD4+ cells are believed to contain the CCR5 modification, though an exact measurement has proven difficult to obtain.
Right. So. That's the science behind the treatment method. But does it actually work?
In a word: Maybe.
The phase 1 study results Mitsuyasu presented involved just nine HIV-infected volunteers, all men and all but two of them Caucasian (the other two were Latino). All of them entered the study with an undetectable HIV-1 plasma viral load, but most had a CD4:CD8 ratio below 1, suggesting a compromised immune system to some degree. This was a long-lived group: The median time living with HIV among the volunteers was 21 years, and most of the volunteers were in their 50s.
The nine volunteers were divided into three study cohorts (of three volunteers each): one cohort received an infusion of 10 billion CD4+ cells; one cohort received 20 billion cells; and one cohort received 30 billion cells.
With such a small study size, it's important to note that it's almost impossible to get any conclusive information on the success of the SB-728 method. Further, the volunteers' response to the therapy was somewhat mixed.
However, on balance, the news appeared good: After a full year of follow-up following the infusion, the volunteers averaged a CD4+ cell count gain of 100 (prior to the treatment, CD4+ cell counts ranged from 269 to 450, so these were not people in a deeply precarious health situation to start with). They also averaged a CD8+ cell count gain of 100; CD4:CD8 ratios fluctuated a bit after the infusion, but hovered right around 1 -- its ideal level -- after a year. Viral load data were not included in the presentation. No marked differences were noted between any of the three cohorts.
The CCR5-modified CD4+ cells appeared to survive (and presumably replicate) within most of the volunteers for at least a year. The median proportion of a volunteer's CD4+ cells that had the modification settled at around 5% through 360 days, after initially spiking to around 14% after the initial infusion. Mitsuyasu pointed out that the CCR5 gene modification persisted in rectal mucosa as well, hovering between 6% and 8%.
Mitsuyasu also provided details on one of the nine patients who volunteered (at request) to interrupt his treatment rather than receive a new infusion of modified CD4+ cells after one year. This allowed the researchers a glimpse at whether SB-728 had long-term staying power. But it's difficult to say what this glimpse showed. The volunteer's viral load spiked from about 5,000 to around 35,000 a few weeks after the interruption began, but then began to drop, and eventually appeared to stabilize around 25,000 by 28 weeks after interruption. CD4+ cell levels initially plummeted from approximately 600 to about 300, then recovered into the 400-500 range. CD8+ cells initially spiked, then appeared to settle; and anti-HIV binding antibodies steadily climbed.
All of that is consistent with a rebound of the volunteer's HIV, but it's unknown to what extent that rebound may have been at least partly ameliorated by the continued presence of those CCR5-modified CD4+ cells. Further muddying the waters is that the volunteer's nadir CD4+ cell count and viral load set point were unknown, so there was no way to know whether his numbers were simply returning to their original, pre-treatment state.
What Mitsuyasu did note, however, was that the presence of modified CD4+ cells inside the volunteer continued to persist through 28 weeks post-interruption -- and even spiked in the first couple of months after interrupting, from 2% to above 6%, coinciding with the time his viral load spiked. This suggests that not only do these modified CD4+ cells persist, but that they're actively replicating (or reactivating) as well.
Finally, the safety data: The SB-728 approach appears remarkably safe, at least by comparison to most antiretrovirals. None of the nine study volunteers reported a single serious adverse event, despite a median follow-up time of 337 days. There were a total of 60 adverse events, almost all of which were mild and the majority of which occurred within 24 hours of the initial cell infusion. Of these events, the researchers deemed 35 to be drug-related; most were tied to the infusion process itself, including headache, chills, fever, sweats, dizziness, fatigue, and a "garlicky body odor" that was related to the cryogenic preservation process for the infused CD4+ cells.
So what we're left with, after wading through all this data, are still a lot of questions. Nelson Vergel walked through many of them when he discussed the preliminary data from this study several months ago, and they all still hold true.
The bottom line is that SB-728 remains an exciting, tantalizing concept -- but as of yet, it's still just a concept. A great deal of additional study will be necessary before we can gain any real confidence in the approach. Ongoing phase 1/2 trials in both aviremic immunologic nonresponders and viremic treatment-naive volunteers will no doubt shed more light on the potential of this process.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.
Copyright © 2011 The HealthCentral Network, Inc. All rights reserved.
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