Cake, candles and a wish for more HIV cures

Cake, candles and a wish for more HIV cures

An HIV workshop pays tribute to Timothy Ray Brown, whose cure 10 years ago fueled research — and hope

Feb. 13, 2017 | By Mary Engel / Fred Hutch News Service

Timothy Ray Brown celebrates his 10th “birthday,” marking the anniversary of the stem cell transplant that made him the first and so far only person in the world to be cured of the virus that causes AIDS.

Robert Hood / Fred Hutch News Service

“It happened, and it was a hard survival. But I’m here.”

With these words, Timothy Ray Brown blew out 10 candles on a chocolate birthday cake as a room full of researchers, activists and people living with HIV cheered.

A decade has passed since the first of two stem cell transplants cured Brown of both leukemia and HIV, making him the first and so far only person to be cured of the virus that causes AIDS. Sunday’s “birthday” celebration, a tradition among transplant cancer survivors, capped a day-long workshop on HIV cure research on the eve of a major HIV scientific meeting, the annual Conference on Retroviruses and Opportunistic Infections, or CROI, being held in Seattle.

The Seattle-born Brown flew in for the workshop and celebration from Palm Springs, California, where he now lives. Later this week, he’ll mark his original birthday, albeit a little early, with his mother. He turns 51 in March.

Dr. Gero Hütter, the German doctor who cured Brown, could not attend Sunday’s party in Seattle but sent a videotaped greeting. At the time of Brown’s transplant, scientists had considered a cure for HIV so unlikely that it took Hütter a year after first reporting the case to get a paper published in a medical journal.

“I think that you all agree with me that Timothy’s case, as a proof of principle, has changed a lot of the field of HIV research,” Hütter said in the video. “Timothy is the motivation for hundreds of researchers, fundraisers and activists to go forward to the big target that HIV/AIDS can be cured.”

But if Brown’s cure inspired the field of HIV cure research, he is also a reminder of the challenges that remain.

‘The Berlin patient’

Brown was diagnosed with HIV in 1995 in Germany, where he was then living. A year later, he went on antiretroviral therapy, a medical breakthrough that transformed HIV from a death sentence to a manageable disease for those who have access to the drugs. It was not until he developed life-threatening leukemia, and chemotherapy failed, that he needed the stem cell transplant in 2007. That’s when Hütter had the idea of trying to cure both diseases at once by finding a donor with a rare gene mutation that blocks HIV’s entry.

In 2008, the cancer returned and Brown required a second transplant. But he has not taken antiretroviral medicine since the first, and today he still shows no signs of either leukemia or HIV. Identified only as “the Berlin patient” in that first paper and in subsequent media reports, Brown went public in 2010, around the time he returned from Berlin to live in the United States, as a way to call attention to the need for cure research.

No one considers a high-risk, high-cost transplant appropriate for the vast majority of people with HIV who don’t also face a deadly blood cancer. Brown’s experience shows why. The second transplant was especially hard on him and required a brain biopsy that left him with some neurological problems. Years of physical and other therapy have helped resolve that, but his eyesight is poor and the harsh chemotherapy that he underwent as part of his “conditioning” for the transplant has left him with nerve damage and balance problems. His disabilities leave him unable to work.

“Mainly, I just want my life to be normal again,” he said Sunday.

Several attempts to replicate Brown’s cure, with and without an HIV-resistant donor, have failed to show the same results. In many cases, patients died from the transplant or of their cancer before it could be determined whether their HIV was cured. In two patients in Boston who received transplants from donors without the protective mutation, HIV rebounded after several months of remission.

 

At Sunday’s workshop, Fred Hutch’s Dr. Hans-Peter Kiem described how he and other researchers are using Brown’s case as a starting point to find a less harsh and more broadly applicable cure. He and Dr. Keith Jerome co-direct defeatHIV, a Hutch-based HIV cure research group that focuses on cell and gene therapy. Their goal is to genetically engineer resistance in an HIV-infected person’s own blood stem cells rather than, as in Brown’s case, using immune cells from a matched donor with the rare HIV-resistant mutation. The group also is working on using

the immune system to eradicate or at least control HIV, just as immunotherapies are beginning to revolutionize cancer treatment.

DefeatHIV is one of six public-private research groups nationwide funded by the National Institutes of Health to research potential HIV cures.

“I really want to thank Timothy,” Kiem said Sunday. “He really inspired and launched cure research.”

‘You give me hope’

When antiretroviral therapy was first introduced in 1996, hopes were high that, taken long enough, the drugs would not just suppress but cure HIV. These hopes were dashed when researchers found that the virus integrates itself into some of the longest-lived cells in the body, forming reservoirs of latent infection that roar back if medication is stopped.

But according to studies presented Sunday by Dr. Merlin Robb of the U.S. Military HIV Research Program, early treatment with combination antiretroviral therapy is at least a step toward curing HIV. Starting treatment very early after infection can reduce the size of the reservoir in the first place and prevent further damage to the immune system, making any cure developed down the road more likely to be effective, Robb said.

Other topics of discussion at the workshop included how and whether antiretroviral treatment can be safely halted under carefully monitored conditions to test if a cure approach is working (do not try this at home) and whether enough females, from mice to humans, are being enrolled in clinical trials to understand how cure approaches may work differently in different genders (no).

The workshop also focused on the how as well as the what and why of cure research. Laurie Sylla, a member of the defeatHIV community advisory board, which co-sponsored Sunday’s workshop, talked about how trust and transparency are key to HIV cure or any clinical trials.

Trial participants “want to know what are the risks we know about, and what are the risks we may not know?” she said. “And they want to there’s a safety plan. What’s going to happen to me if I participate in this? How quickly are we going to be able to identify that I’m having a bad reaction? And how quickly are you going to do something for me if that happens?”

Pat Migliore, another defeatHIV community advisory board member who has been living with HIV since 1984, recounted a list of fears involved in HIV cure: that long-time survivors like her will be left behind. That postmenopausal women will be left behind. That people of color will be left behind.

“Until there’s a cure for everybody in this world, there’s a cure for nobody,” she said.

As to whether there will be a cure in her lifetime, Migliore, 60, confessed to skepticism.

But, she added, “What gives me hope is seeing all of you. And Timothy, you give me hope.”

A role model, again

For all of the setbacks he has suffered and the disabilities he continues to confront, Brown, an early gay activist who once modeled himself after Boy George, retains his dry sense of humor and wicked sense of fun. He finds purpose in his role as the only member of a singular club and cheerfully embraces his role as symbol of hope.

And on Sunday, he stepped forward to be a role model once again. The only person in the world who has been cured of HIV revealed for the first time publicly that, several years ago, he started taking PrEP — for “pre-exposure prophylaxis — a daily pill that lowers the risk of acquiring HIV. Although Brown’s immune system is now HIV-resistant, he could become reinfected should he be exposed to a less-prevalent strain of HIV that uses a different kind of receptor to enter cells.

Brown recognizes how devastating it would be to people who take hope in his cure for him to have HIV again. And if the most famous HIV-free person in the world can be an example to others at risk of contracting HIV to use PrEP, then Brown is up for the task.

As Moses Nsubuga, an HIV activist and musician from Uganda in town for the workshop and CROI, sang a Ugandan birthday song and everyone else gamely joined the chorus, Brown basked in the appreciation and declared he could handle blowing out the 10 candles.

“It’s OK,” he said, before taking a big breath. “It has worked out.”

 

Join the conversation about an HIV cure on our Facebook page. Learn more about HIV/AIDS research at Fred Hutch.

Mary Engel is a staff writer at Fred Hutch. Previously, she covered medicine and health policy for newspapers including the Los Angeles Times, where she contributed to a series that won a Public Service Pulitzer for health care reporting. She also was a fellow at the year-long MIT Knight Science Journalism program. Reach her at mengel@fredhutch.org or follow her on Twitter, @Engel140.

Are you interested in reprinting this story? Be our guests! We want to help connect people with the information they need. We just ask that you link back to the original article, preserve the author’s byline and refrain from making edits that alter the original context. Questions? Email editor Linda Dahlstrom at ldahlstr@fredhutch.org.

Can immunotherapy cure HIV?

Hutch News
http://www.fredhutch.org/en/news/center-news/2016/08/can-immunotherapy-cure-hiv.html

Can immunotherapy cure HIV?

A revolution in cancer care may offer clues to a cure or remission for HIV/AIDS

Aug. 8, 2016 | By Mary Engel / Fred Hutch News Service

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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 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 harness 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 tried 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 destroys 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 tried 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 second 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 experience 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 knowledge 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.”

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Dr. Larry Corey
Fred Hutch file

When the firehouse catches fire

Early in his career, Corey’s work on the first antiviral treatment for herpes paved the way for HIV therapies that in 1996 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” throughout the body. 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 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 tough 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 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.

In 2007 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 rare gene mutation that confers natural resistance to the virus. Brown stopped taking antiretroviral drugs after the first transplant in 2007 and continues to show 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 new information presented 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 60 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 throughout 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 show 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 carefully monitored research study 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 second person in the world after Brown cured of HIV were dashed when the virus came back eight months later.

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UC San Francisco’s Dr. Timothy
Henrich led ‘Boston patients’ study
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 study 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 blow 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 new 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 20 or 40 cells,” Henrich said to Steinkohl. “That’s all it took. That was depressing scientifically but also highly 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 body, like smallpox, the body always shows you that at the end of the day it can clear that virus and show 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 seeing on this stage is a commitment to trying 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 symposium with Barré-Sinoussi.

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Dr. Chris Peterson presents his research at AIDS 2016
conference in Durban, South Africa. A photo of
“Berlin patient” Timothy Ray Brown is projected on the
screen behind him.
Photo by Robert 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 technique that employs molecules called zinc-finger nucleases and return 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 trying 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, wanted 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 first non-government funders of HIV research, was the first to appreciate the importance of a scientific poster presented at a 2008 conference to little notice by other researchers, scientific journals or the popular press. It was the first public report of Brown, then known only as “the Berlin patient.”

“My goal is to go back to amfAR with at least five solid ideas that we want to work on,” Johnston told the auditorium full 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.

Mary Engel is a staff writer at Fred Hutchinson Cancer Research Center. Previously, she was a writer covering medicine and health policy for newspapers including the Los Angeles Times, where she wrote the editorials for a series that won a Public Service Pulitzer for health care reporting. She also was a fellow at the year-long MIT Knight Science Journalism program. Reach her at mengel@fredhutch.org or follow her on Twitter, @Engel140.

Are you interested in reprinting this story? Be our guests! We want to help connect people with the information they need. We just ask that you link back to the original article, preserve the author’s byline and refrain from making edits that alter the original context. Questions? Email editor Linda Dahlstrom at ldahlstr@fredhutch.org.

defeatHIV Receives Second Round of Funding from NIH

This article was originally published on fredhutch.org:
http://www.fredhutch.org/en/news/center-news/2016/07/HIV-cure-program-fred-hutch-expanded.html

Fred Hutch HIV cure program extended, expanded

DefeatHIV receives second five-year grant from NIH to research gene and cell therapies

July 13, 2016

By Mary Engel / Fred Hutch News Service

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Dr. Keith Jerome, left, and Dr. Hans-Peter Kiem are the co-directors of defeatHIV.
Photo by Robert Hood / Fred Hutch News Service

The National Institutes of Health today awarded a second five-year round of funding to defeatHIV, a public-private research group based at Fred Hutchinson Cancer Research Center that has spent the last five years investigating the use of genetically modified, HIV-resistant blood stem cells as a potential cure for the virus that causes AIDS.

“We’re excited and honored to be able to continue defeatHIV’s work and keep Fred Hutch at the center of HIV cure research, particularly in the area of cell and gene therapy,” said defeatHIV co-director Dr. Keith Jerome, a Fred Hutch virologist.

The new $23.5 million award will allow the group to tackle three new approaches that build on its earlier work. They include:

  • Exploring CAR T-cell therapy, a type of immunotherapy that already is being hailed as a potent anti-cancer weapon, against HIV, in partnership with Seattle-based biopharmaceutical company Juno Therapeutics
  • Using gene therapy to induce production of a synthetic “super antibody” to target HIV
  • Adding a therapeutic vaccine to boost the proliferation and function of genetically modified HIV-resistant cells

All three new tactics have in common a focus on using the immune system to eradicate or at least control HIV.

“We’ve learned that the immune response — the patient’s immune system — plays a critical role in controlling HIV, just like in cancer,” said defeatHIV co-director Dr. Hans-Peter Kiem, a Fred Hutch stem cell transplant and gene therapy researcher. “It’s set the stage for the next generation of studies to further mobilize and harness the immune system to fight HIV.”

An ambitious agenda

DefeatHIV was one of six groups nationwide to receive a total of $150 million over the next five years from the NIH’s Martin Delaney Collaboratory: Towards an HIV-1 Cure program. That is double the number of research collaborations funded in the program’s first iteration in 2011.

The three original groups ­— based at Fred Hutch, the University of California San Francisco and the University of North Carolina at Chapel Hill — received funding again for new projects. Three new groups were added, based at George Washington University in Washington, D.C., the Wistar Institute in Philadelphia and Beth Israel Deaconess Medical Center in Boston.

Named in honor of a late HIV/AIDS activist who served on the advisory committee for the National Institute of Allergy and Infectious Diseases, or NIAID, the Martin Delaney program strongly encourages collaboration within and among research groups and between scientists and private industry. The goal is to translate research into the clinic as rapidly as possible.

“The two greatest challenges remaining in HIV/AIDS research are finding a cure and developing a safe and effective preventive vaccine,” said NIAID Director Dr. Anthony S. Fauci in a statement announcing the awards. “A simple, safe and scalable cure for HIV would accelerate progress toward ending the HIV/AIDS pandemic.”

Moving therapies to clinical trials is an ambitious aim considering that until about eight years ago, curing HIV was considered all but impossible.

The biggest success story for HIV came in 1996, when combination antiretroviral treatment turned the virus from a certain death sentence to a chronic manageable disease, at least for those who have access to the drugs and can tolerate them. But hopes that this treatment would eventually cure infection were dashed when scientists learned that the virus, which integrates itself into a person’s own DNA, can hide out in cells, dormant and out of reach of the drugs. Some likened HIV to the proverbial cockroach that can survive a nuclear blast: Stop treatment, and the virus comes back.

But in at least one case — that of Timothy Ray Brown — the virus did not roar back after the blast. In 2008, the world learned about the Seattle-born Brown, who while living in Berlin had undergone two grueling bone marrow transplants to treat acute myeloid leukemia. In what proved to be a successful attempt to also cure Brown’s HIV infection, his Berlin doctor found a stem cell donor who carried two copies of a rare gene mutation that confers natural resistance to the virus. Brown stopped taking antiretroviral drugs after the first transplant in 2007 and shows no sign of HIV.

In its first five years, defeatHIV used Brown’s cure as a blueprint for developing a less toxic therapy than the one he endured by seeking to genetically engineer resistance in an infected person’s own immune cells. In preclinical experiments, Kiem’s lab has successfully modified blood stem cells using a gene editing technique that employs molecules called zinc-finger nucleases and returned the resistant stem cells to repopulate the immune system.  Research into this approach will continue under a separate five-year grant to Kiem’s lab from the National Heart, Lung and Blood Institute, a division of the NIH. The biopharmaceutical company Sangamo Biosciences, which developed zinc-finger nucleases, will continue as a defeatHIV partner.

New approaches, new partners

The first new approach — engineering HIV-resistant and anti-HIV T cells — will be led by Fred Hutch virologist Dr. Larry Corey and immunology and infectious disease experts Drs. David Rawlings and Thor Wagner of the University of Washington and Seattle Children’s, along with Juno Therapeutics.

Researchers at Fred Hutch and elsewhere have been working on still-experimental therapies that genetically reprogram patients’ own T cells — a type of white blood cell that searches out and destroys pathogens — 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 of CAR T cells for cancer, with promising early results.

DefeatHIV proposes to transfer this approach from cancer to HIV by producing CAR T cells that target markers expressed by cells that harbor HIV.

Corey, whose early work in treating herpes laid the groundwork for antiretroviral treatment for HIV and who now leads the world’s largest network for testing preventive HIV vaccines, will discuss the CAR T-cell approach as the keynote speaker at the upcoming 2016 Conference on Cell and Gene Therapy for HIV Cure on Aug. 4-5 at Fred Hutch.

The second new approach — genetically engineering the production of a synthetic broadly neutralizing antibody — will be led by Dr. Michael Farzan, professor of immunology and microbial science at the Scripps Research Institute in Jupiter, Florida. Farzan made headlines last year for developing a lab-made molecule that is more powerful than any antibody humans produce against HIV. In preclinical models, Farzan’s lab used a virus to insert a gene into muscle cells to direct production of this “super antibody” and showed that it protected against HIV infection. Farzan described his research at the 2015 Conference on Cell and Gene Therapy for HIV Cure, hosted by defeatHIV at Fred Hutch, which cemented the scientists’ decision to work together, according to Jerome.

The defeatHIV proposal calls for pairing each of these two new strategies with a latency-reversing agent developed by the biotechnology company Gilead Biosciences to “wake up” the reservoir of dormant HIV so infected cells can be targeted by CAR T cells or Farzan’s broadly neutralizing antibodies. Reducing the viral reservoir is seen as key to an HIV cure.

Preclinical and limited human trials in Kiem’s and others’ labs have already shown that genetically modifying stem and T cells not only makes them resistant to HIV infection but improves immune function overall. So for the third new tactic, defeatHIV will seek to boost that immune response by adding a therapeutic vaccine. (A vaccine given before infection is called a preventive vaccine; it helps healthy people set up defenses against infection. Therapeutic vaccines are designed to treat people after they are infected by strengthening the body’s natural immune response. So far, neither type of vaccine has been successfully developed for HIV.)

“Even a small percentage of gene-edited cells help orchestrate an immune response against the virus,” said Jerome. “So we thought we could build on that going forward by adding a therapeutic vaccine.”

Leading the vaccine effort will be University of Washington microbiologists Dr. Jim Mullins, who already has a vaccine in clinical trials, and Dr. Deb Fuller.

In addition to its new partners, Jerome and Kiem stressed the continued partnership with the volunteer community members who make up its Community Advisory Board, or CAB.

“Our CAB is the model for community involvement around cure. It’s the greatest partner we could hope for,” said Jerome. “Representatives from the CAB are at pretty much all of our planning meetings to listen, to advise as we talk about clinical trials, for information flow in both directions. They wrote an incredibly strong section of the proposal for the grant.”

Hope and caution

The plan is that at least one and maybe more of these three strategies will be ready for clinical trials in the next four to five years, Jerome and Kiem said. And unlike clinical trials that tried to replicate Timothy Ray Brown’s transplant cure, the new strategies will not require testing in people with both HIV and cancer.

“Before, we talked about that we would have to test in patients with malignancies because we needed high-dose irradiation and chemotherapy for the transplant procedure,” harsh treatments that would only be appropriate if needed to also treat cancer, said Kiem.

In fact, efforts elsewhere to replicate Brown’s cure in patients who needed stem cell transplants as a last-resort cancer treatment have so far failed to show the same results. In part, these are often very ill patients to begin with; in most cases, they died from the cancer or the transplant before it could be determined whether their HIV was gone. Brown remains the only known person in the world to be cured of HIV.

As excited as the Hutch researchers are about the new, less toxic approaches and as optimistic as they are about getting to clinical trials, they remain cautious when it comes to using the word “cure,” whether for cancer or HIV.

“We’ve become a bit more careful in terms of the words ‘HIV cure,’” said Kiem, who works with both cancer and HIV patients. “It is difficult to determine whether every single cancer cell has been eliminated in the body after a bone marrow transplant. Yet we know we can cure the cancer because in many patients it does not return even after five or 10 years, and we know the immune system plays a critical role.”

HIV and the HIV reservoir pose a similar challenge. So far, there are no good tests or markers to tell for sure whether HIV might be still hiding in a few cells.

“It will take time to determine whether HIV has the potential to return, and we think just like in cancer, therapies establishing a solid immune system and response that can recognize HIV will be an important and critical part in our HIV cure effort,” Kiem said. “If HIV can be made undetectable, it is first like a remission and then after several years we will know whether it is a cure, just like in cancer. Many investigators have also come to the conclusion that this is a very reasonable first step and expectation.”

——–

Mary Engel is a staff writer at Fred Hutchinson Cancer Research Center. Previously, she was a writer covering medicine and health policy for newspapers including the Los Angeles Times, where she was part of a team that won a Pulitzer for health care reporting. She also was a fellow at the year-long MIT Knight Science Journalism program. Reach her at mengel@fredhutch.org.

Are you interested in reprinting or republishing this Fred Hutch story? Be our guests! We want to help connect people with the information they need. We just ask that you link back to the original article (see link at top of page), preserve the author’s byline and refrain from making edits that alter the original context. Questions? Email editor Linda Dahlstrom at ldahlstr@fredhutch.org.

Conference on Cell & Gene Therapy for HIV Cure 2016

3rd Annual Conference on Cell & Gene Therapy for HIV Cure to be held August 4-5, 2016 in Seattle, WA

WEBSITE
ctg4hivcure2016.org

DATES
Pre-Conference Community Event: August 3, 2016
Conference: August 4-5, 2016

LOCATION
Fred Hutchinson Cancer Research Center
Seattle, WA USA

We are pleased to announce the 3rd Conference on Cell & Gene Therapy for HIV Cure will be held August 4-5, 2016 in Seattle, WA. This conference aims to bring much needed attention to HIV cell and gene therapies by uniting an international roster of esteemed scientists to share and discuss novel treatments and research using these innovative modalities.

Featured speakers include:

KEYNOTE
Lawrence Corey, MD
President and Director Emeritus
Fred Hutchinson Cancer Research Center
Lawrence Corey Endowed Chair in Medical Virology
Professor, Laboratory Medicine and Allergy and Infectious Diseases
University of Washington

PLENARIES
Warner C. Greene, MD, PhD
Direcot, Senior Investigator
Gladstone Institute of Virology and Immunology
Nick and Sue Hellmann Distinguished Professor of Translational Medicine
Professor of Medicine, Microbiology and Immunology
University of California, San Francisco

Timothy Henrich, MD
Assistant Professor, Department of Medicine
Division of Experimental Medicine
University of California, San Francisco

Mark Kay, MD, PhD
Dennis Farrey Family Professor
Department of Pediatrics and Genetics
Vice Chair for Basic Research (Pediatrics)
Stanford University

 

This two-day international conference will be held at the campus of Fred Hutchinson Cancer Research Center in Seattle, WA. A pre-conference Community Event, organized by the defeatHIV Community Advisory Board, will be held the evening of August 3, 2016.

We look forward to building on the success of the first two conferences, held in 2014 and 2015, and invite HIV and cell and gene therapy researchers, clinicians, young investigators and trainees including pre- and post-doctoral fellows, to participate. Scholarships are available to trainees. We also continue to partner with community advocates, including HIV community advisory board (CAB) members, and are pleased to offer a limited number of community sponsorship and volunteer opportunities.

Please visit our conference website for more details!

CGT4HIVCure2016.org

Publication Spotlight: Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates

Genome editing in hematopoietic stem and progenitor cells (HSPCs) is a promising novel technology for the treatment of many human diseases. Here, we evaluated whether the disruption of the C-C chemokine receptor 5 (CCR5) locus in pigtailed macaque HSPCs by zinc finger nucleases (ZFNs) was feasible. We show that macaque-specific CCR5 ZFNs efficiently induce CCR5 disruption at levels of up to 64% ex vivo, 40% in vivo early posttransplant, and 3% to 5% in long-term repopulating cells over 6 months following HSPC transplant. These genome-edited HSPCs support multilineage engraftment and generate progeny capable of trafficking to secondary tissues including the gut. Using deep sequencing technology, we show that these ZFNs are highly specific for the CCR5 locus in primary cells. Further, we have adapted our clonal tracking methodology to follow individual CCR5 mutant cells over time in vivo, reinforcing that CCR5 gene-edited HSPCs are capable of long-term engraftment. Together, these data demonstrate that genome-edited HSPCs engraft, and contribute to multilineage repopulation after autologous transplantation in a clinically relevant large animal model, an important step toward the development of stem cell-based genome-editing therapies for HIV and potentially other diseases as well.

 

 

http://www.ncbi.nlm.nih.gov/pubmed/26980728

Publication Spotlight: A curative regimen would decrease HIV prevalence but not HIV incidence unless targeted to an ART-naïve population

HIV curative strategies currently under development aim to eradicate latent provirus, or prevent viral replication, progression to AIDS, and transmission. The impact of implementing curative programs on HIV epidemics has not been considered. We developed a mathematical model of heterosexual HIV transmission to evaluate the independent and synergistic impact of ART, HIV prevention interventions and cure on HIV prevalence and incidence. The basic reproduction number was calculated to study the potential for the epidemic to be eliminated. We explored scenarios with and without the assumption that patients enrolled into HIV cure programs need to be on antiretroviral treatment (ART). In our simulations, curative regimes had limited impact on HIV incidence if only ART patients were eligible for cure. Cure implementation had a significant impact on HIV incidence if ART-untreated patients were enrolled directly into cure programs. Concurrent HIV prevention programs moderately decreased the percent of ART treated or cured patients needed to achieve elimination. We project that widespread implementation of HIV cure would decrease HIV prevalence under all scenarios but would only lower rate of new infections if ART-untreated patients were targeted. Current efforts to identify untreated HIV patients will gain even further relevance upon availability of an HIV cure.

 

http://www.ncbi.nlm.nih.gov/pubmed/26908162

Publication Spotlight: Detection of treatment-resistant infectious HIV after genome-directed antiviral endonuclease therapy

Incurable chronic viral infections are a major cause of morbidity and mortality worldwide. One potential approach to cure persistent viral infections is via the use of targeted endonucleases. Nevertheless, a potential concern for endonuclease-based antiviral therapies is the emergence of treatment resistance. Here we detect for the first time an endonuclease-resistant infectious virus that is found with high frequency after antiviral endonuclease therapy. While testing the activity of HIV pol-specific zinc finger nucleases (ZFNs) alone or in combination with three prime repair exonuclease 2 (Trex2), we identified a treatment-resistant and infectious mutant virus that was derived from a ZFN-mediated disruption of reverse transcriptase (RT). Although gene disruption of HIV protease, RT and integrase could inhibit viral replication, a chance single amino acid insertion within the thumb domain of RT produced a virus that could actively replicate. The endonuclease-resistant virus could replicate in primary CD4(+) T cells, but remained susceptible to treatment with antiretroviral RT inhibitors. When secondary ZFN-derived mutations were introduced into the mutant virus’s RT or integrase domains, replication could be abolished. Our observations suggest that caution should be exercised during endonuclease-based antiviral therapies; however, combination endonuclease therapies may prevent the emergence of resistance.

 

http://www.ncbi.nlm.nih.gov/pubmed/26718067

Publication Spotlight: Safety and Efficacy of Combination Antiretroviral Therapy in Human Immunodeficiency Virus-Infected Adults Undergoing Autologous or Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

The ability to continue combination antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-infected patients undergoing hematopoietic cell transplantation (HCT) for treatment of hematologic malignancies is likely a critical factor in preventing the establishment of an HIV reservoir in transplanted stem cells. Thus, we studied the feasibility of continued antiretroviral therapy in our HIV-infected patients undergoing autologous or allogeneic transplantation. All HIV-infected adults undergoing HCT for hematologic malignancy at Fred Hutchinson Cancer Research Center between 2006 and 2014 were included; most were enrolled in a prospective clinical study to monitor HIV reservoirs after transplantation (NCT00968630 and NCT00112593). Non-nucleotide reverse transcriptase inhibitor or integrase-strand inhibitor-anchored antiretroviral therapy regimens were continued or selected before HCT by infectious disease physicians. Plasma HIV RNA was measured every other day for the first 2 weeks after transplantation and then every 2 weeks. Missed doses of cART and reasons for changing the cART regimen during the post-transplantation hospitalization were documented through review of inpatient pharmacy records. Seven autologous and 8 allogeneic transplantations were performed. In 9 transplantations, the cART regimen was not altered after HCT and no doses were missed. In 2 patients who required alterations in their cART regimen because of development of acute renal failure (n = 1) and small bowel obstruction (n = 1) after HCT, enfuvirtide was used as a bridging component of the regimen. Plasma HIV RNA remained suppressed during the first 28 days in 12 of 15 transplantations, and no patients had a plasma HIV RNA >1000 copies/mL during long-term follow up. Non-nucleotide reverse transcriptase inhibitor- and integrase-strand inhibitor-based cART are safe and effective in HIV-infected persons during the peri-HCT period. Most patients undergoing HCT were able to continue cART without missed doses. Sustained HIV viremia and emergence of resistance were not detected.

 

 

http://www.ncbi.nlm.nih.gov/pubmed/26265463

Conference on Cell and Gene Therapy for HIV Cure 2015

WEBSITE
ctg4hivcure2015.org

DATES
August 13-14, 2015

LOCATION
Fred Hutchinson Cancer Research Center
Seattle, WA USA

 

We are pleased to announce the 2nd Conference on Cell & Gene Therapy for HIV Cure will be held August 13-14, 2015, in Seattle, WA. This conference aims to bring much needed attention to HIV cell and gene therapies by uniting an international roster of esteemed scientists to share and discuss novel treatments and research using these innovative modalities.

Featured speakers include:

KEYNOTE
David Baltimore, PhD
President Emeritus
Robert Andrews Millikan Professor of Biology
California Institute of Technology
Nobel Prize in Physiology or Medicine (1975)
National Medal of Science (1999)

PLENARIES
Dan H Barouch, MD, PhD
Professor of Medicine
Harvard Medical School
Director, Center for Virology and Vaccine Research
Beth Israel Deaconess Medical Center

Michael Farzan, PhD
Vice Chairman
Professor, Department of Immunology and Microbial Science
Scripps Research Institute

Matthew Porteus, MD, PhD
Associate Professor, Pediatrics – Stem Cell Transplantation
Member – Bio-X, Child Health Research Institute, Stanford Cancer Institute
Stanford University

This two-day international conference will be held at the campus of Fred Hutchinson Cancer Research Center in Seattle, WA. The audience will consist of national and international scientific researchers, early investigators, post docs, and graduate students. Registration Scholarships and Travel Grants are available.

Please visit our conference website for more details!

CGT4HIVCure2015.org

 

defeatHIV investigator wins prestigious International AIDS Society (IAS) Award:

Dr. Christopher Peterson, staff scientist in the lab of defeatHIV Co-PI Dr. Hans-Peter Kiem at Fred Hutch, was awarded the IAS Young Investigator Award for his recent HIV Cure research.
His abstract was one of over 2,500 competing for this prize, which is to be presented at this year’s annual IAS Conference on HIV Pathogenesis, Treatment, and Prevention in Vancouver, Canada. Dr. Peterson’s research has focused on using zinc-finger nucleases (ZFNs) to interfere with a specific receptor, CCR5, on the membranes of white blood cells. HIV uses CCR5 as a doorway into the cells. Upon receptor inhibition by the ZFNs, the gene-modified cells are naturally resistant to HIV, as the virus no longer has a means to enter and infect the cells.
The success of Dr. Peterson’s research is a promising advancement for defeatHIV, which modeled this approach after the case of Timothy Ray Brown (aka the Berlin Patient). Mr. Brown was cured of HIV by an allogenic bone marrow transplant from a donor whose cells expressed a mutation in the same receptor specifically targeted by Dr. Peterson and colleagues using ZFNs. Significant hurdles must be overcome before this approach can be applied clinically, however Dr. Peterson’s research is a crucial step forward in our mission to eradicate HIV. Read more about Dr. Peterson, his research, and the award HERE.