Crux as Crock
One Shot Immune-Based Therapy Would Be Patient Dream -- and Pharma's Dread
Interview with Richard Jefferys
When Markets Fail
In an attempt to balance last month's immune-based pipeline update, which might have been a bit heavy on cytokine therapies and other immunologic esoterica, this month we feature a more conversational approach to what some see as the holy grail of IBT research: a therapeutic vaccine, most likely administered on a (very) infrequent basis, that would render life-long antiretroviral therapy anachronistic.
TAGline: I couldn't help but notice that while you included quite a few therapeutic vaccine candidates in your immune-based therapies table, they weren't mentioned within the text of your report. Personally, I've been regaling friends for the past six years or so with stories of how a therapeutic vaccine would arrive on the scene and save us from these nasty antiretrovirals. You're making me look bad!
Richard Jefferys: I sort of scrunched the therapeutic vaccines all together just because the basic principle behind them is the same and I was a bit worried about space.
TAGline: And also because you've lost faith in the biological rationale?
RJ: No, not at all. There have been major advances in basic T-cell immunology which firmly support the rationale for trying the approach which I think is very important. Brigitte Autran, specifically, has just recently gone on record as very optimistic. A lot of other researchers remain skeptical, though.
TAGline: Advances? I confess I'm a bit behind in my European Journal of Immunology reading. What advances exactly?
RJ: Basically, HIV-specific CD4 T cells seem to get sort of stuck in a pre-memory state in all but long-term non-progressors, so untreated progressive disease is like a sort of persistent, low-level acute infection.
TAGline: So an effective therapeutic vaccine then would, what, wake up a "post-memory" immune system?
RJ: In a manner of speaking. Most of the T-cell activation that accompanies uncontrolled HIV replication may be the result of naive T cells getting activated, not memory T cells. Activated naive T cells take several weeks to mature into memory T cells with characteristic, and potentially important, functional properties such as IL-2 production and proliferative capacity, and this rarely seems to happen in untreated HIV infection. Creating a more functional HIV-specific memory T-cell pool has become the goal of many research teams now -- including Autran's.
TAGline: Is there any precedent for this? I guess I mean, any evidence that this is even achievable?
RJ: When HAART is initiated, you do see evidence that some activated T cells complete their differentiation into IL-2-producing "central memory" HIV-specific CD4 T cells, but the numbers remain below that seen in long-term non-progressors. The data comes from Guisseppe Pantaleo's lab, although I'm putting a froth of speculation on top.
TAGline: This is getting heavy. Let's go for a bottom line here.
RJ: Bottom line: A good vaccine can almost certainly help increase the numbers of these [IL-2-producing "central memory" HIV-specific CD4 T] cells, hence potentially better preparing the immune system to control HIV when HAART is stopped. Whether this pans out, of course, remains to be seen.
TAGline: So, wait. We're back to HAART followed by treatment interruption followed by a therapeutic vaccine? Why not just the vaccine -- from the get go?
RJ: What seems to inhibit the differentiation of memory T cells is persistent viral replication, so vaccinating in the setting of uncontrolled viremia is unlikely to generate the sort of memory response that people are after. Immunizing while an individual is on HAART -- and allowing enough time for the memory T-cell response to develop or "mature" -- looks like the better way to go. One concern I have about many current studies is that the timing of immunizations and HAART interruptions may be too concentrated to allow this maturation process to fully complete. For example, many protocols have used monthly immunizations and/or interrupted HAART just a few weeks after the last immunization. According to basic immunologists, intervals of at least three months would be a lot better. Quite literally, developing memory T cells like a nice long rest before going into action.
TAGline: I'm trying to recall your chart on this. You mentioned Merck and Glaxo, but the Glaxo product hasn't even been in humans has it? Seems Aventis is furthest along, but isn't that the ALVAC vaccine that failed in preventive studies?
RJ: ALVAC is in a few therapeutic studies, but hasn't shown much promise. The first ALVAC efficacy trial as a preventive just got underway, although the inclusion of AIDSVAX as a booster is a big problem. Glaxo's construct is in phase I as a preventive, but I don't think therapeutic trials have started yet. There are therapeutic trials planned through the ACTG for Merck's adenovirus-based vaccine (phase I/II), a DNA construct made by the NIH's Vaccine Research Center (phase I) and RIGHT's Dermavir (pre-clinical) constructs which I can detail a bit more since they will be open around the country and potentially, uh, joinable.
Therapeutic Vaccines Candidates Mentioned in This Article
VRC-HIVDNA009-00-VP Gag/Pol/Nef/multiclade Envs (A, B, C)
Vaccine Research Center/NIAID
Autologous dendritic cells pulsed w/ALVAC
Research Institute for Genetic & Human Therapy (RIGHT)
DNA + IL-12 or IL-15
Tat/Nef/gp120 in ASO2A adjuvant
TAGline: So, big picture, the science is ripe. What needs to happen, then, to accelerate the development of something we can use?
RJ: I think the major issue in terms of IBT incentives now is not any longer the unknowns, but rather the potential competition with the lucrative market for antiretrovirals.
TAGline: Are we talking cannibalism-phobia here?
RJ: Otherwise known as fear of shooting yourself in the foot with something that may be good for medicine but bad for business. Truth be told, an effective therapeutic vaccine would ideally reduce reliance on drug therapy, and -- to get in touch with my inner conspiracy theorist -- it's possible that this makes the approach rather unpopular with members of the Retrovirus mafia who have nice cozy relationships with the big antiretroviral manufacturers.
TAGline: Meaning we can only expect an effective immune-based therapy or therapeutic vaccine if it doesn't cut into Big Pharma's other sales? Lovely.
RJ: Well, maybe. Also, immunological principles suggest that a good therapeutic vaccine should not have to be administered chronically, and this isn't the sort of thing Big Pharma is very fond of developing. Look at the history of drug development for other life-threatening illnesses: a one-shot cure is the last thing you want -- unless perhaps you can charge millions of dollars a pop for it. Where Big Pharma is concerned, chronic daily dosing of expensive medication is much more rewarding.
TAGline: I guess that means the best immune-based therapy for Big Pharma would be one that doesn't really work? Then we're screwed, basically. Unless some Deaniac outsider upstart can come in a trail blazing and take on the big vested interests?
RJ: Merck sort of seems to be taking the high ground in pursuing their construct -- in the odd way that Merck does sometimes. There is also an emerging movement towards re-evaluating approaches to R&D so that, when market forces and good medicine clash, other mechanisms can fill the gap.
TAGline: An emerging movement. I like the sound of that. Sounds similar to something Paul Bellman approached me about recently. Might make for an interesting future TAGline article. And what of the other big players? Glaxo? Wyeth?
RJ: I suspect that GlaxoSmithKline has just jumped on the therapeutic vaccine bandwagon. I'm skeptical as to whether they really intend to take their product the whole way. It's a pretty shitty immunogen. Wyeth has some DNA+cytokine adjuvant constructs that are likely to be studied as therapeutics.
TAGline: And what about my white knight scenario?
RJ: Yes, of course. The more optimistic flipside to all of this is that the small biotech outfits could potentially make money from this sort of approach more easily than the bigger companies -- and may therefore be more likely to step in now that the basic science is giving them some reason to think that therapeutic vaccines (and perhaps some other immune-based therapies) could provide sufficient benefit to be licensable.
TAGline: Blessed are the lithe and the big risk takers.