Treatment Horizons by Chael Needle
An immunotherapy candidate stimulates T-cell responses via patient-specific antigens
Previous studies have established immunotherapy candidate AGS-004, both as a single agent and in concert with antiretrovirals, to be safe and well-tolerated, lacking toxicity, and, importantly, as conferring an effective immune response—an atypically long delay in viral rebound and a significantly reduced viral load when compared to pre-antiretroviral therapy levels. Now, in light of research breakthroughs that show potential for flushing out latent reservoirs and improved assays to monitor viral and therapeutic impact, the objective for AGS-004 has shifted in the direction of cure for those already infected with HIV—that is, the “complete eradication of replication-competent cells,” as Dr. Charles Nicolette, the Chief Scientific Officer and Vice President of Research and Development for Argos Therapeutics, maker of AGS-004, so deftly puts it.
Data on AGS-004 was recently presented at the Towards an HIV Cure Symposium at the International AIDS Society conference in Kuala Lumpur, Malaysia. “What we’re trying to do here is fundamentally different from what has been attempted in the past. When people hear the word ‘cure’ they should be skeptical about it,” Dr. Nicolette says about “cure”-claim fatigue among the HIV community, “but that really is what we’re aiming at. And, in theory, we have the tools and the strategy that could potentially lead there.”
Though effective at viral suppression, antiretrovirals have not been shown to be able to restore effective HIV-specific immune responses (CD4 and CD8 T cell responses) capable of eliminating all virus. Thus, HIV disease remains chronic, rather than dismantled and inoperable thanks to a restored immune system. That restorative potential, in part, lies with immunotherapeutic agents.
A popular immunotherapy approach has been to load dendritic cells (DC) with HIV antigens (via viral and non-viral carriers) and immune modulators in order to stimulate immune cells, and especially CD8 T cells, to increase and broaden their response.
However, HIV, due to its ability to mutate and its high genetic variability, is often not easy to make recognizable because it has multiple and patient-personalized antigens that go undetected. The common single-antigen approach, therefore, is limited; it may elicit an immune response but not significantly reduce the viral load because the immune system isn’t “seeing” the virus in all its complexity. “Using one sequence of an antigen to raise an immune response against the virus when you have thousands or tens of thousands in a patient is just poorly matched to the patient’s viral load. So, we see no impact,” says Dr. Nicolette.
With its branded Arcelis Technology, Argos loads a patient’s own dendritic cells with a sample of messenger RNA (“mRNA”)—in this case, a patient’s particular RNA encoding for CD40L and for all of the mutated species of HIV antigens Gag, Nef, Rev, and Vpr—derived from each patient’s pre-ART plasma via a one-time outpatient procedure involving a process called leukapheresis. These dendritic cells, now loaded and then intradermally reinjected, can potentially prime immune responses to the entire antigenic repertoire.
Personalizing the antigen payload so that the agent is perfectly matched to each patient’s viral load is only part of the strategy; the engineered dendritic cells, specially programmed for a patient’s damaged immune system, also deliver immune stimulators. “The patient’s immune system is not normal, so you have to engineer it to be able to function normally in that environment. What we have done is engineer certain signals that would normally come from the patient’s own immune machinery into our product so that our product behaves as if it’s in a normal immune environment,” explains Dr. Nicolette. “After you inject the cells into the patient, they migrate to the nearest lymph nodes and they begin communicating with the patient’s CD8 T cells. And CD8 T cells are the ones that will actually go out and do the dirty work of killing an infected cell, once they’re educated.…The product basically educates the CD8 cells to go out and find anything that looks like what they were instructed to recognize.”
Summarizes Dr. Nicolette: “Our experiment was to answer the question: If you could raise an immune response that was matched, that was 100 percent relevant to that patient’s viral species, can you impact viral load? And the answer to that was ‘yes.’ To our knowledge, this was the first reporting of an immunotherapy that was able to reduce viral load by the levels we observed.”
But, says Dr. Nicolette, continuing down this development path does not make a lot of sense because it’s not expected that AGS-004, or any immunotherapeutic agent, on its own would clear the virus from latent reservoirs, where it persists in dormancy and can be reactivated if antiretroviral therapy stops.
Researchers at Argos, a North Carolina-based company, are planning to see if HDAC inhibitors, part of a new class of reservoir mobilizers, could be used in conjunction with AGS-004. Argos is currently working with Dr. David Margolis of the University of North Carolina, who has tested the HDAC inhibitor called vorinostat in HIV patients and demonstrated that it can activate the latent reservoir. The goal is to see if this plus AGS-004 is an effective combination. “If a cell is infected but not producing the viral proteins, it’s going to be invisible. It’s going to be missed. So combining this approach with something that makes those cells visible makes a lot of sense. Our ultimate goal will be to flush out and eliminate all of the infected cells.”
Argos is currently working on a clinical protocol with Dr. Margolis and could possibly start recruiting for clinical trials later this year or early next year. “In contradistinction to our previous studies there would be no requirement for anyone to interrupt their drugs unless we had a strong inclination that the virus had been entirely cleared. So I think that’s good news for patients who are willing to participate in clinical studies. We’re not asking them to put a lot of skin in the game in terms of any kind of potential clinical risk in terms of drug interruption.”
Chael Needle wrote about HarborPath, a patient-assistant drug access organization, in the June issue.