Tuesday, March 1, 2011

Don't Say Cure: Questions for Jay Lalezari, MD

 Jay Lalezari, MD

Jay Lalezari is a longtime AIDS researcher from San Francisco. In “We Were Here,” a new film about the early days of the AIDS epidemic, he appears in a photo of the founders of UCSF's legendary Ward 86, the AIDS hospital ward that became a model for the world. These days, he runs dozens of clinical trials on HIV and hepatitis as Director of Quest Clinical Research in San Francisco.

Yesterday morning, February 28, Dr. Lalezari presented groundbreaking data from an AIDS eradication study at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.
Here’s how his study worked: Dr. Lalezari removed some CD4 cells from six, brave, long-term survivors with zero viral load, then sent the cells to a lab where the  CCR5 receptors were removed from the cells using zinc finger technology--a pioneering gene manipulation technique invented at Sangamo Biosciences. The lab froze the newly CCR5-less cells, and mailed them back to Dr. Lalezari, who thawed them out and infused them back into the patients.  Remember—the Berlin patient was treated with a bone marrow transplant using a donor whose cells lack the CCR5 receptor. CCR5 is one of the major receptors that allows HIV to infect cells.
The goal? To see if the system (remove cells, mail, alter, freeze, mail, thaw, reinfuse) actually worked. To learn whether the therapy was safe. And to see if the altered cells spread throughout the body, and engrafted. The long-term goal is to give the patients a reservoir of HIV-resistant cells.
The study succeeded on all counts. Says Dr. Lalezari, “We showed that infusion of modified cells was safe. And we‘ve shown a number of promising data results—increased CD4 count [5 of the 6 patients received increases of 100 CD4 cells for the length of the study], expansion of the cells by three fold, persistence of the infused cells, and the migration of cells to the gut.” The gut is a major reservoir of HIV.
KK: What are next steps?
JL: I caution people about throwing around the C word –I work with people with AIDS every day. I know the effect we have when we talk about a cure as researchers. That’s different from what you can say as an activist.

This could all eventually lead to nothing. But we’ve proven the loop can be completed. The next step is to test the therapy in treatment-naïve patients. What will those cells do in the presence of virus? Presumably they will expand even further. In the presence of HIV, they obviously have a selective growth advantage. We should see even more expansion [than the data presented today].

The whole shooting match is what happens to those viral loads. If those viral loads come down, you and I are living in a different universe. If they don’t, I don’t think there’s any gray area.

The new study will enroll 14 patients who are either treatment-naïve or have been on previous therapy but then stopped. They must have CD4 cell counts over 500 and be in an early stage of disease.

KK: How are you able to accrue patients easily when many research sites struggle to enroll patients in cure studies?

JL: It’s all about how you handle people. People who come to my office get a lot of loving. We treat people with respect. We have a great staff. We have dogs running around. We’re not big and academic, with waiting areas and paperwork. People respond to that—they respond in kind. We have great employees, too. [Quest’s oldschool web site kind of tells the story: http://www.questclinical.com/ ]

KK: What are some of the logistical barriers to this research for you?

JL: I’m running 23 studies right now. Too often, researchers end up designing studies that are unenrollable. Because the people who are designing the studies are giving priority to scientific integrity without any real thought about how patients might see  a study design or what might be in their interest. And there isn’t a balance between the competing needs of what you really need as a secondary endpoint and what is practical and feasible for patients. For Hepatitis C, for example: Study designers might really need to know Day 28 viral load. But then they decide they also want to know about the effect of interferon and riboviron. And then they can’t enroll that study. If they just stuck to the primary endpoint they’d be ok. But people pile on secondary endpoints.

KK: Have you met Gero Huetter?

JL: I haven’t.  The fact that re-transplanted the the Berlin Patient after the first transplant failed to cure the cancer [but had cured the AIDS] shows what kind of person he is. Thank you, Gero.

But the Berlin Patient was about the virus running out of targets because of the ablation of the patient’s immune system. The new research is going to be about generating HIV–specific effector cells.

KK: Can people volunteer for your new AIDS study?

JL: If you live in the Bay Area and you’re treatment naïve, give me a call.

KK: If you had $15 million to spend on AIDS cure research, what would you do?

I would want to understand elite controllers better. What are the immune correlates of elite controllers?

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