Dr. Sarah Schlesinger
Associate Professor, The Rockefeller University

Race for the Cure

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Schlesinger and her colleagues, in conjunction with the Rockefeller University, the Bill and Melinda Gates Foundation, and the NIH are working on a vaccine that directly targets dendritic cells.

Dr. Sarah Schlesinger

For over ten years, Dr. Sarah J. Schlesinger has been actively engaged in HIV/AIDS and HIV vaccine research. She is currently conducting clinical trials to test a new vaccine called ADMVA, designed to stimulate immune responses and thereby prevent HIV from ever being contracted. A graduate of Wellesley College and Rush Medical College, Schlesinger has been interested in medical science since she was a teenager. As a high school student attending a lecture at Rockefeller University, she boldly asked scientist Ralph Steinman for a job in his laboratory.

Schlesinger worked in Steinman's lab just a few years after he and Zanvil Cohn published their famous discovery of dendritic cells. She then went on to head her own dendritic cell lab at Walter Reed Hospital from 1990 to 2002. With new knowledge about the ability of dendritic cells to orchestrate the body's immune response, Schlesinger and her colleagues are attempting to develop customized immune therapies to target specific infections such as HIV/AIDS, malaria and influenza; certain cancers; and autoimmune diseases.

Sarah Schlesinger: The first is a DNA vaccine, which is called Advac, which we first tested in 2003, 2004. DNA vaccines are wonderful in that they are very safe. They’re cheap. They don’t require a cold chain. They work great in mice, and they don’t work very well in people. So we tested that, and it was modestly immunogenic, which is as good as one might hope for DNA vaccines. The idea was it would be combined with ADMVA, which is based on the smallpox vaccine.

It’s modified vaccine Ankara, so we know that the smallpox vaccine induces good immunity, so the idea like with the adeno viral vector is to use the smallpox vaccine as a vector. And so that’s what we did, and we conducted a trial of that alone, and then a small trial of the two together. Those are being moved forward by Dr. Ho and his team in China, and they’re moving into advanced development. So you have Phase One trials, which is what we conducted, which are largely safety. We also, of course, looked at immunogenicity, because we’re not going to give something to people and not figure out if it’s doing something. And the they move into larger trials. In order to move into larger trials, you have to move into a population of people who are getting infected, because you need to look for efficacy.

These vaccine were always designed to move forward for efficacy trials into China. Because of the number of infections in the developing world versus the United States, most efficacy trials have been and will continue to be conducted in the south or the developing world. So I’d stay in New York. No. I’ve gone to China a couple of times, but my work is primarily here at the Rockefeller Hospital. So currently what I’m working on, which is very exciting, and this is under the rubric of the grant challenges and global health grant mechanism through the Bill and Melinda Gates Foundation, and the FNIH, the Foundation for NIH, and Ralph Steinman, who I mentioned 17 million times in this conversation, is the intellectual force behind this and the PI of the grant, and I have the privilege of doing the clinical part. But we are developing a vaccine that directly targets dendritic cells.

So I think I mentioned earlier that for any vaccine to work, we know it has to get to dendritic cells. You can demonstrate with a lot of them that they do to greater or lesser degrees. But we’ve sort of decided to take the bull by the horn and make a vaccine that knows how to find dendritic cells. It’s what called rational vaccine design, and I think it’s brilliant. And I can say that because I didn’t think of it. I get to conduct it, but I didn’t figure it out. The idea is we have a monoclonal antibody that’s directed against what’s called DEC05. DEC205 is on dendritic cells. It’s a marker that’s special on dendritic cells that was discovered by Ralph and my friend and colleague, Michelle Nussenzweig [ph?] many years ago. So they made an antibody to it. So that antibody goes into the body and immediately finds that receptor. And so then we’ve hooked up to that monoclonal antibody genes or the antigen for HIV.

The one we’re starting with is GAD, which is the core, which is conserved, and there are lots of reasons that’s a good one to start with. So we have a monoclonal antibody that knows how to find dendritic cells hooked up to our HIV antigen. This is a protein. And so we’ve been moving that concept forward in small animals, and now we are going to be moving into the clinic. And so we have our first conversation about this with the FDA in August, and I’m hoping that we’ll be in the clinic by year’s end. So the idea is we have to be smarter than nature. We can’t, because natural infection doesn’t confer protection, we have to figure a way around what the virus that causes AIDS HIV has learned how to do. And to do that, we want to directly target dendritic cells, the cells that we know orchestrate immunity.


Recorded on: June 10, 2008