|contrasting combative strategies (hydroxyurea and IL-2)
Jun 5, 2004
I am attaching to you an article that is most interesting. How do you feel about the concept of combining hydroxyurea and IL-2? How many years real-time are we away from seeing this in practice?
Positives for Positives Winter 2003/2004, Number 28
Interview With Franco Lori, M.D. Research Institute for Genetic and Human Therapy (RIGHT), Washington, DC and Pavia, Italy
Listen to the full interview recorded © by IFARA: RealAudio (6.6MB) | MP3 (5.8MB)
P4P: We're here with Dr. Franco Lori of the Research Institute for Genetic and Human Therapy (RIGHT) based in Washington, DC and Pavia, Italy. Dr. Lori has been doing a lot of work in immune-based therapies and immune-modulating drugs. Dr. Lori, perhaps we could start with immune-based therapies, and you could describe some of the things you're working on at the Institute.
Dr. Lori: Yes, the concept we are working on is to use drugs that act on the immune system that could become useful component adjuncts and synergize with existing antiretrovirals. There are many ways to work with and around the immune system. The one we chose is to work with drugs that have anti-inflammatory properties, because I think there is enough evidence out there that over-activation of the immune system is probably the leading pathogenetic cause of HIV/AIDS and of the progression of the disease, so that if we could decrease the amount of over-activation and "cool down" the immune system, which is really too hot and heated up, then we could benefit from that intervention in terms of better durability of antiretroviral therapy, better survival, and better quality of life for the patients. We are trying to go in a somewhat different direction than people dealing with antiretrovirals usually do, but we think it's a good compliment to the existing therapies.
P4P: I know in your immune-modulating drugs, certainly HU1 has been around for a long time, but I also understand that you're doing some work with, microphenolic acid ... am I saying that correctly?
Dr. Lori: That's right.
P4P: Could you describe some of that work?
Dr. Lori: The news with hydroxyurea is that we finally completed our 702 study. It was a large study on different doses and schedules of the drug. To our surprise we found out that the lowest dose, which is 600 mg once a day or 300 mg two times a day, almost half of what we were used to employing in HIV therapy, is not only less toxic as one would imagine, but it is by all parameters we measured more effective. It has a high degree of increase of CD4 count, and the antiviral efficacy is far superior and statistically significant. So, I think we have to revisit the concept of the use of hydroxyurea with a dosage that is much lower than the one we were using, which frankly was becoming too toxic especially when we were moving towards 1,200 mg. That was way too much. That was the wrong direction to take. So I think we have to revisit the concept of the use of hydroxyurea at low dosage, because it's less toxic and much more effective.
Now microphenolic acid is another drug, and please keep in mind that when we talk about cytostatic drugs, although they more or less act with similar mechanisms, they are all different, one from the other one, like antiretrovirals. So microphenolic acid has slightly different characteristics. It's more often immune-suppressant, whereas hydroxyurea is a cytostatic drug. The cytostatic drug really stops cell division or reduces cell division, so that there are less CD4 lymphocytes ready to be infected by HIV, there is less immune activation. Microphenolic is more often immune-suppressant and has been used in the past as such. We have to figure out exactly what the difference is between all these drugs and choose the best candidates based on their properties.
P4P: Do you think there's a possibility of using hydroxyurea and microphenolic acid in combinations?
Dr. Lori: That's an interesting question. I've always been reluctant to consider a combination of immune-modulating drugs before understanding the mechanisms, but I know that people in France, for example, have combined hydroxyurea and IL-2, which is something I would never have done myself, but they have very good results. So, yes, it is a possibility. But I would like to understand first how it works, and second the dosage. I think the 702 study fixing the optimal does of hydroxyurea has been very important for us, because we can do damage by using the drugs in the wrong concentration. We learn a lot when we dose and schedule properly those drugs, and ... microphenolic is going to require some work before we understand what the best dosage of the drug is.
P4P: Is microphenolic ... is that ... where is that at in terms of the approval process at this point? Are we talking in vitro at this point, Phase 1 I&D application, where are we at in terms of moving that along into clinical practice?
Dr. Lori: We have to appreciate that both hydroxyurea and microphenolic are drugs that are approved for other diseases, so they are out there, they are on the shelf. But you cannot use them for HIV except for compassionate use or in the context of clinical trials. So from that standpoint it's an unusual situation. It's not a brand new drug, it's a drug where we know a lot about toxicity and a lot about how to use it, but still we have to do the proper trials in order to have it accepted by the FDA as an anti-HIV drug. It's difficult to draw analogies with T-20, for example, which has been developed from scratch. I think we are somewhat in between. We still need a good Phase 2 study and a Phase 3 study before we can ever think about approving the drug for HIV use.
P4P: In terms of things that you are finding most striking or most newsworthy coming out of this conference ... is there anything in particular that is most striking or interesting for you?
Dr. Lori: I think that in the last 2 or 3 years we are more in the mode of conferences that are setting small steps ahead rather than really striking ones. And it's healthy for the field, but not so healthy for the patients that are waiting so anxiously for news. I don't think we can really say that there is anything that strikes as absolutely outstanding in the news. But I think that we are understanding a lot more about the drugs and how to use them. I think we're understanding a lot more about the immune system, which is really what interests us, and I think that we're understanding better how to modulate the immune system in order to have it as the best ally instead of the worst enemy of anti-HIV treatment. We're interested in following the field of therapeutic immunization, because we are convinced that the immune system has something to say and to do way beyond the primary infection. The immune system is active and can be exploited for good cause, I would say almost until the very end, if not the very end. When the immune system is still there it can still be helpful to us, and if you can find a vaccine that would prevent infection, because the vaccine is really for prevention, that could push toward that direction, I think it would serve the cause and many people are moving towards that goal, and quite successfully.
P4P: Last year Dr. Judy Lieberman presented some work on RNA interference, and talking to other folks at this conference so far this year, they are saying that this is a great scientific tool for them in their work. Are you finding uses for or the concept of RNAi helpful in your work at all?
Dr. Lori: We don't use RNAi. I've been following the field and Judy's work, however, which I think is excellent. I think that there are issues on the delivery. I've been involved in the use of oligonucleotides, anti-sense back at the beginning of the '90s, so I'm familiar with the problems, and one of the issues in using DNA or RNA or genes or genetic constructs, is really the delivery. That's what created such a big problem for gene therapy, after all. So what we thought would be very useful, and that's the very concept of the therapeutic immunization that we are proposing, is to use DNA. And instead of trying to find out how to deliver it 100 percent to infected cells, delivery of even 10 percent or 5 percent to immune-competent cells -- because immune-competent cells, their job is going to be to expand the information to create a cascade of immune reaction to an antigen that is present even in a minority of cells, because that's the nature of the immune system. So what is a disadvantage in the oligonucleotides, in the gene therapy, in the RNAi field, can become of very important value for therapeutic immunization. Take those genes, deliver them to the immune-competent cells, especially antigen-presenting cells, for example the dendritic cells, Langerhans cells on the surface of the skin, target those. It doesn't matter if you don't achieve 100 percent efficiency. You don't even want to achieve 100 percent efficiency, just a small efficiency would be enough to trigger a strong and robust immune response. I think that's a reasonable analogy for what Judy and other people are doing, and what we are doing. We are still focusing on DNA and genetic progress.
P4P: Doctor Lori, thank you so much for your time here today. It's always a pleasure.
Back to the Winter 2003/2004 issue of Positives for Positives.
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Response from Dr. Pierone
My feeling is that combining hydroxyurea and IL-2 is not a good thing and using them together would clearly be in the experimental realm. Hydroxyurea has modest antiretroviral activity and suppresses the immune system to some degree. IL-2 stimulates the immune system and raises CD4 counts. Both agents have significant toxicities and can be tricky to use.
It is possible that these agents may eventually find a role to play in HIV management once the experimental trials are concluded. If they do make it to approval I think it will be for limited situations.
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