Can immunotherapy cure HIV?
Can immunotherapy cure HIV?
Dr. Rowena Johnston, vice president and director of research for the Foundation for AIDS Research, addresses the third annual Conference on Cell and Gene Therapy for HIV Cure at Fred Hutch.
Photo by Robert Rubber hood / Fred Hutch News Service
HIV cure researchers and advocates met at Fred Hutchinson Cancer Research Center last week to explore whether immunotherapy — treatments that corset the immune system to fight cancer — could play a role in bringing about a cure or a long-term remission for HIV, the virus that causes AIDS.
“CAR T cells have the potential to kill HIV-infected cells,” said Fred Hutch virologist and 35-year HIV research veteran Dr. Larry Corey in the keynote address to the third annual Conference on Cell and Gene Therapy for HIV Cure. “Twenty years ago, they were attempted for HIV. They didn’t work much, but now we know how to do them better.”
Corey was referring to a still-experimental type of immunotherapy in which patients’ own T cells — a type of white blood cell that searches out and ruins pathogens — are genetically re-engineered with synthetic receptors called chimeric antigen receptors, or CARs, to kill cancer cells bearing a particular marker. There are now dozens of clinical trials underway at Fred Hutch and elsewhere of CAR T cells for leukemia and lymphoma, with promising early results.
Years ago, Corey said, scientists attempted T-cell therapies against HIV without much success. Now, building on advances made in cancer and other diseases, he wants to revisit these and other approaches that engage the immune system to go after HIV. DefeatHIV, the Hutch-based HIV-cure research group that hosted last week’s conference, just received a 2nd five-year round of federal funding to explore CAR-T and other immunotherapies against HIV, including boosting the immune system via a therapeutic vaccine and genetically engineering the production of synthetic broadly neutralizing antibodies.
“We’re a big center for CAR T therapy. We have significant practice here using this technology for cancer, especially leukemia and lymphoma,” said defeatHIV co-director Dr. Hans-Peter Kiem, a Fred Hutch stem cell transplant and gene therapy researcher. “It combines the skill we’ve gained on gene therapy to enhance immunotherapy.”
As another speaker, University of Pennsylvania microbiologist Dr. James Riley, put it, “To cure HIV, we’re going to need a better immune system.”
Fred Hutch file
When the firehouse catches fire
Early in his career, Corey’s work on the very first antiviral treatment for herpes paved the way for HIV therapies that in one thousand nine hundred ninety six turned the virus from a certain death sentence to a chronic disease. But while antiretroviral drugs lower the level of HIV to undetectable levels, they are not a cure. The virus persists in a dormant state in “reservoirs” via the figure. If therapy is stopped, HIV roars back.
One of the challenges of boosting the immune system to attack that HIV reservoir is that HIV attacks the immune system very first. It targets a type of “helper” T cell involved in initiating an immune response.
“HIV kills the human cells that normally control infections,” said Dr. Thor Wagner of the University of Washington and Seattle Children’s Hospital, who, with Corey, is working on the defeatHIV CAR T-cell project. “It’s like a firehouse that catches on fire. It’s a harsh fire — or infection — to fight.”
Still, Wagner said, it’s feasible to engineer T cells that can both kill HIV-infected cells and be resistant to HIV infection, adding that such CAR T cells in combination with other strategies might help achieve HIV remission.
Scientists already have proof that the immune system can cure HIV or at least drive it into long-term remission. Just as bone marrow transplantation provided the very first definitive example of the human immune system’s power to tame — and even cure — cancer, it did the same for the very first — and so far only —HIV cure, that of Timothy Ray Brown.
In two thousand seven and again in 2008, the Seattle-born Brown, living in Berlin, underwent two grueling bone marrow transplants to treat acute myeloid leukemia. Because he also had HIV, his German doctor sought out a stem cell donor who carried two copies of a infrequent gene mutation that confers natural resistance to the virus. Brown stopped taking antiretroviral drugs after the very first transplant in two thousand seven and proceeds to showcase no signs of HIV.
Until now, attempts to duplicate Brown’s cure in other people with HIV who also needed a bone marrow transplant for cancer have not been successful; most of the very ill patients died either of the cancer or the transplant. But fresh information introduced at the conference in Seattle and last month at a large AIDS conference in Durban, South Africa, offers hope that Brown’s cure can be repeated.
‘You turned my sadness to pride’
A transplant, already a high-risk procedure for cancer patients, is even risker for people who also have HIV, with mortality rates approaching sixty percent, according to Dr. Annemarie Wensing, a clinical virologist at the University Medical Center in Utrecht, the Netherlands.
That’s why Wensing and others, including Dr. Gero Hütter, the oncologist who cured Brown, formed a collaborative project called EpiStem to guide clinicians via Europe doing stem cell transplants in people with both cancer and HIV.
The project also studies the effect of bone marrow transplantation on HIV. In Durban and again in Seattle, Wensing reported on three patients who survived both the cancer and the transplant. Two now showcase no signs of HIV after extensive and sensitive testing and one shows just traces of the virus. Because just one patient had an HIV-resistant donor, Wensing hypothesizes that graft-vs.-host disease may have helped clear or at least reduce the HIV reservoir, much as a graft-vs.-leukemia effect is critical in achieving a cancer cure or remission.
But while the three EpiStem patients’ HIV may be cured or in remission, the only way to tell for sure is to take them off their antiretroviral medication, as was the case with Brown. But that has not yet been done, in part due to lessons learned about the physical and emotional effects of stopping the anti-HIV drugs.
In March 2013, as part of a cautiously monitored research explore at Boston’s Brigham and Women’s Hospital, Gary Steinkohl went off antiretroviral therapy three years after having a bone marrow transplant for cancer. His hopes of becoming only the 2nd person in the world after Brown cured of HIV were dashed when the virus came back eight months later.
UC San Francisco’s Dr. Timothy Henrich led ‘Boston patients’ investigate
Photo by Bo Jungmayer / Fred Hutch News Service
“When the virus returned, I went to a dark place,” said Steinkohl, who attended the conference and spoke at a public forum with that study’s lead scientist, Dr. Tim Henrich, now with the University of California San Francisco.
Henrich had worked hard not to stoke false hope in Steinkohl and one other examine participant, still known only as Patient A. At the forum, he told Steinkohl, “The most difficult thing I’ve ever had to do in my professional life was to tell you and Patient A that your virus was back.”
Steinkohl acknowledged what a gargle it had been, but added, “You told me what I had given the scientific field was invaluable. You turned my sadness to pride that I had helped you. And in helping you, I was helping us,” meaning everyone with HIV.
The challenge of curing HIV
Stem cell transplants are too risky and expensive to be considered a large-scale HIV cure. But as Henrich pointed out, studying people like Steinkohl and the fresh EpiStem patients provide key insights into the role of the immune system that may be applicable to other immunotherapies.
One of the lessons learned was how few HIV-infected cells were needed for the infection to come back.
“We were able to get your reservoir to a point so low that when it did come back after you went off therapy, it looked like it came from twenty or forty cells,” Henrich said to Steinkohl. “That’s all it took. That was depressing scientifically but also very informative.”
No wonder that at last month’s conference in Durban, Dr. Françoise Barré-Sinoussi, one of the discoverers of the virus, said, “Achieving [an HIV] cure is one of the greatest scientific challenges ever undertaken.”
Also in Durban, Dr. Anthony Fauci, the longtime director of the National Institute of Allergy and Infectious Diseases, part of the U.S. National Institutes of Health, expounded on that challenge.
“This is not like any other infection that we have faced,” he said. “In virtually every virus that attacks the assets, like smallpox, the assets always shows you that at the end of the day it can clear that virus and showcase sustained immunity to the virus. HIV doesn’t give us that. We have to do something that nature has never done.”
Gesturing to Barré-Sinoussi and other HIV experts on the panel, Fauci added, “I don’t think that anybody on this table can tell you that we will have a cure for HIV. But what you’re witnessing on this stage is a commitment to attempting this challenge.”
The efforts going into finding a cure for HIV, despite the immense challenges, do not go unnoticed by the people to whom it matters most.
“You don’t get thanked enough for this long slog you’re going through,” Steinkohl told researchers gathered in Seattle.
‘We absolutely want to hear your ideas’
Other immunotherapy approaches discussed at the Durban conference included the use of checkpoint inhibitors, which block a mechanism that cancer cells use to shut down the immune system. Drugs developed to “unblock” these inhibitors have now been licensed for use against advanced melanoma. Several observational trials are underway of patients with both HIV and melanoma who are receiving such drugs, according to the University of Melbourne’s Dr. Sharon Lewin, who co-chaired the Durban cure symposiumwith Barré-Sinoussi.
Dr. Chris Peterson presents his research at AIDS two thousand sixteen conference in Durban, South Africa. A photo of “Berlin patient” Timothy Ray Brown is projected on the screen behind him.
Photo by Robert Rubber hood / Fred Hutch News Service
Also in Durban and again in Seattle, Fred Hutch’s Dr. Chris Peterson, a staff scientist in Kiem’s lab, reported on successful efforts in preclinical models to modify blood stem cells using a gene- editing technology that employs molecules called zinc-finger nucleases and comeback the resistant stem cells to repopulate the immune system. His work is part of an effort to use Brown’s cure as a blueprint for developing a less-toxic therapy by seeking to genetically engineer resistance in an infected person’s own immune cells.
“We’re attempting to make the case of Timothy Ray Brown more applicable to more people,” Peterson said.
That’s what Dr. Rowena Johnston, vice president of amfAR, the Foundation for AIDS Research, wished to hear. She told conference attendees that her group plans to spend $100 million over the next five years to develop a scientific basis for an HIV cure.
AmfAR, co-founded by actor and AIDS activist Elizabeth Taylor and one of the very first non-government funders of HIV research, was the very first to appreciate the importance of a scientific poster introduced at a two thousand eight conference to little notice by other researchers, scientific journals or the popular press. It was the very first public report of Brown, then known only as “the Berlin patient.”
“My aim is to go back to amfAR with at least five solid ideas that we want to work on,” Johnston told the auditorium total of scientists, postdocs and graduate students. “We absolutely want to hear your ideas.”
Join the conversation about finding a cure or long-term remission for HIV on our Facebook page.
