Looking for 'a multitude of ways to cure HIV'

HIV researchers draw hope from cancer immunotherapies — and inspiration from Timothy Ray Brown
photo of Dr. Carl June
Pioneering CAR T-cell therapy researcher Dr. Carl June, director of the Center for Cellular Immunotherapies at the University of Pennsylvania's Perelman School of Medicine and a co-director of the Parker Institute for Cancer Immunotherapy, delivered the keynote address at the Conference on Cell and Gene Therapy for HIV Cure at Fred Hutch. To his right is gene therapy and stem cell transplant specialist Dr. Hans-Peter Kiem, co-director of the Fred Hutch-based defeatHIV. Photo by Robert Hood / Fred Hutch News Service

Before he gave the keynote talk at an HIV cure conference in Seattle last week, University of Pennsylvania researcher Dr. Carl June checked to see how many clinical trials testing CAR T-cell therapies against cancer were listed on the National Institutes of Health’s website ClinicalTrials.gov. He found 217 worldwide. Then he checked to see how many were listed for HIV. He found only one — in China.

“We need to change that,” June said.

His audience was already on it.

The Conference on Cell and Gene Therapy for HIV Cure, held at Fred Hutchinson Cancer Research Center and hosted by the Hutch-based defeatHIV research group, drew about 200 scientists from around the country, many of whom are studying CAR T-cell therapies and other ways to harness the powers of the immune system to cure HIV.

Clinical trials underway at Fred Hutch and elsewhere of CAR T cells for cancer have shown promising early results. These still-experimental therapies genetically reprogram a patient’s own T cells — a type of immune cell that searches out and destroys abnormal or infected cells — with synthetic receptors called chimeric antigen receptors, or CARs, to target cancer or a selected pathogen. One such therapy developed in June’s lab for advanced childhood leukemia is on the brink of becoming the first CAR T-cell therapy to win U.S. Food and Drug Administration approval.

June first became interested in T cells as an oncology fellow at Fred Hutch from 1983 to 1986, where he came to study bone marrow transplantation, “the first form of immunotherapy,” he told conference attendees.

Just as bone marrow transplantation provided the first definitive example of the human immune system’s power to tame and even cure cancer, it did the same for the first — and so far only — HIV cure, that of Timothy Ray Brown. Brown had been living with HIV for a decade when he was diagnosed with acute myeloid leukemia. In 2007, after chemotherapy failed to arrest the cancer, he underwent a bone marrow transplant in Berlin, where he lived. It took a second transplant to drive his cancer into remission, but 10 years later, the “Berlin patient,” as he was known at first, shows no sign of either leukemia or HIV.

Brown, whose face showed up on virtually every PowerPoint presentation delivered, joined defeatHIV co-directors Dr. Hans-Peter Kiem, a stem cell transplant and gene therapy specialist, and Dr. Keith Jerome, an infectious disease expert, to open the conference. He sat in the front row for the next two days and was thanked from the podium by many scientists, including June, who told him, “I’m very glad you’re advocating for research.”

Now in its fourth year, the conference drew HIV experts, people living with HIV and their advocates, and cancer researchers who have devoted their careers to improving stem cell transplants. Here are some highlights.

‘Why has lightning not struck twice?’

Although no one considers stem cell transplants appropriate for the vast majority of people with HIV, researchers have been interested in seeing if Brown’s cure could be repeated in other patients with HIV and cancer who need a transplant anyway.

But as if to underscore how serious both leukemia and bone marrow transplants are, early attempts to duplicate Brown’s results were unsuccessful largely because the very ill patients died either from the cancer or the transplant. 

photo of Dr. Catherine Bollard
Dr. Catherine Bollard Robert Hood / Fred Hutch News Service

“Why has lightning not struck twice?” asked Dr. Catherine Bollard, a bone marrow transplant specialist with Children’s National Health System and George Washington University School of Medicine and Health Sciences in Washington, D.C.

Possibly, it has. At an international HIV/AIDS meeting in Paris in July, scientists reported on a European cohort of patients with HIV who have successfully undergone bone marrow transplants for advanced leukemias and lymphomas. Five such patients have been followed for more than two years and appear to be HIV-free.

But while their HIV may be cured or in remission, the only test is to take them off their antiretroviral medication — something that has not yet been done because of lessons learned several years ago when two Boston patients were believed to be cured and taken off daily treatment only to have their HIV come back.

In the meantime, researchers continue to try to tease out how, exactly, the transplant cured Brown and how they can fashion a less risky approach suitable for people who aren’t also facing life-threatening cancers.

Weighing the factors

One of the biggest challenges to curing HIV is the existence of so-called “reservoirs” of dormant, HIV-infected cells. Combination antiretroviral therapies developed in the mid-1990s suppress active virus, turning HIV from a certain death sentence to a chronic, manageable disease. But these drugs don’t affect the HIV reservoirs, and even a tiny number of latently infected cells are enough to re-seed infection if a person with HIV stops taking lifelong medication.

Brown has been off medication for 10 years and — although reservoirs are notoriously difficult to find, much less measure — the virus has not returned. Before his transplant, he underwent conditioning, an intense chemotherapy and radiation regimen that destroys the immune system to make room for transplanted immune cells to grow. Could that pretransplant conditioning have also destroyed his HIV reservoir? Was it the donor that his German doctor located, whose cells carried a rare, HIV-resistant mutation? Afterward, he developed graft-vs.-host disease, or GVHD — a serious, often fatal condition in which the newly donated immune system attacks the patient’s body as “foreign.” What about that?

Research from Fred Hutch’s Dr. Chris Peterson, who works in Kiem’s lab, found that conditioning may play less of a role than first believed, which is good news, given how hard it is to go through. Conditioning before stem cell transplants for cancer patients is done for two purposes: to kill cancer cells and to make room for the donor immune cells. For HIV, Peterson showed in preclinical models that total body irradiation did not have much of an impact on the size of the viral reservoir.

“These results suggest that the focus going forward should be on a conditioning regimen that is less toxic, focusing not on killing the reservoir but just making room for engraftment,” he said. “The side effects of conditioning are just not worth it. And as anyone who’d gone through it or knows someone who’s gone through it knows, it’s not fun.”

Oregon Health and Sciences University researcher Dr. Jonah Sacha, who like Peterson works on preclinical models of HIV, believes that GVHD did play a key role. His theory prompted a question from Brown.

“Why do you think it was the GVHD that cured me?” he asked.

“We know that the graft-vs.-leukemia effect is so potent,” Sacha said.

A pivotal early study on leukemia patients who had bone marrow transplants showed that patients with nonidentical twin donors who developed GVHD had lower rates of cancer recurrence, suggesting a graft-vs.-leukemia effect — that is, the transplanted immune system did not merely replace the one destroyed by conditioning but actually played a role in curing leukemia. But Sacha assured Brown that, as with immunotherapy research in cancer, HIV cure researchers are looking for less-toxic ways to harness that effect.

As for Bollard, she believes that bone marrow transplant specialists should put a higher priority on finding donors that carry the resistance gene that Brown’s donor did. June, who does HIV as well as cancer research, is working on genetically engineering such a mutation in a patient’s own T cells, and Fred Hutch’s Kiem is working on a similar approach in stem cells.

Innovations in the works

For now, CAR T cells are labor-intensive and highly individualized — June calls them “personalized serial killer cells.” But just as cars — as in automobiles — went from being hand-built to factory-made, he predicted that T-cell therapies would become mass-produced as well.

“Since we’re in Seattle, I’ll talk Microsoft,” he said. “We’re Windows 1.0 for CAR T cells now. We’ll have a series of innovations in this area and an increase in sophistication.”

And CAR T cells are not the only innovation on the table. In addition to exploring CAR T-cell therapies, defeatHIV is investigating using gene therapy to induce production of a synthetic “super antibody” to target HIV and adding a therapeutic vaccine to boost the proliferation and function of genetically modified HIV-resistant cells. And, along with defeatHIV, the National Institutes of Health has funded five other public-private HIV cure research groups that are focusing on ways to kick the viral reservoirs awake, studying other immunotherapy approaches used in cancer such as drugs known as checkpoint inhibitors, and developing nanoparticle “backpacks” to deliver virus-killing T cells.

Talk at the conference included these and other approaches, including research on a slow-release form of antiretroviral therapy that would work in combination with the CRISPR gene-editing tool and a study on broadly neutralizing antibodies that may be able to stop the establishment of the HIV reservoir in infants born with HIV if given within the first two days of life. (To date, three children have been reported to be HIV-free after very early treatment with antiretroviral therapy, though in one the virus returned. Scientists say it's too early to know if the other cases are cures or long-term remissions.)

Also presenting at the conference was social scientist Dr. Karine Dubé of the University of North Carolina’s Gillings School of Global Public Health, who spoke of the need to keep HIV clinical trials “patient-centered” and to address concerns about the risks of taking part in HIV cure research, particularly of interrupting antiretroviral treatment. And as is typical of HIV conferences, nonscientists representing and advocating for people with HIV were introduced and applauded.

“One of the things we feel strongly about is involving the community,” said Jerome at the conference opening.

photo of Timothy Ray Brown, the first person cured of HIV
"I think there will be a multitude of different ways to cure HIV," said Timothy Ray Brown, the first and so far only person to be cured. "Brilliant scientists working toward a cure for HIV will find a way or ways to cure it.” Photo by Robert Hood / Fred Hutch News Service

The keynote advocate

If June was the keynote speaker at the conference, Brown was the keynote advocate. He listened attentively to each talk, asked questions and, during breaks, posed for selfies with scientists, many of whom thanked him from the podium for his inspiration.

A native of Seattle whose mother still lives here, Brown, who now lives in California, has developed close relationships with defeatHIV scientists and staff members and is a regular visitor to the Fred Hutch campus. But many scientists who work on HIV cure had never actually met the man behind their research.

Bollard’s response was typical.

“I think Timothy Ray Brown gave a fantastic talk this morning,” she said from the podium before giving one of the plenary talks. “I’ve used his slide forever. It was an honor to hear him speak.”

Fred Hutch’s Dr. Leslie Kean, also a stem cell researcher, echoed that refrain.

“We’re all here because of Timothy Ray Brown,” she said. “He inspires everything we do. [His cure] was the first time we thought there could be an answer.”

Brown never set out to be an icon. Still, he has embraced the role that was handed to him with dedication and uncommon grace. Consider what he said at the conference’s opening:

“What does my cure mean for the HIV-positive community? It gives hope to people.

“In my personal life, I don’t wake up in the morning and think, ‘Oh, I’m cured of HIV. Oh, I’m in long-term remission of acute myeloid leukemia.’ But I think that I’m helping people with being able to deal with their own infections.

“I’m on Facebook and I get a lot of questions from people: ‘What do I do now that I became positive?' I say, 'Take your medication. Follow your doctor’s advice and stay on medication. Don’t deviate from that. You will have a long life that is pretty much equal to anyone else.’  A lot of people still think having HIV means you’re going to die. That’s not the case.

“One day there will be a cure. Not through what I went through — I wouldn’t wish that on my worst enemy. But I think there will be a multitude of different ways to cure HIV. Brilliant scientists working toward a cure for HIV will find a way or ways to cure it.”

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Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.

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