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.

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

fund
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

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 CAB: Meeting March 2014

defeatHIVCAB meetings March-June 2014_flyer

defeatHIV CAB Meeting

Tuesday March 4, 2014  |  5:30-7:30 PM

Cal Anderson House

400 Broadway
Seattle, WA 98112

RSVP TO:  206-667-5810 or mlouella@fhcrc.org

The defeatHIV Community Advisory Board (CAB) invites you to join us on Tuesday, March 4th at our next monthly CAB meeting.

Agenda items include planning for our upcoming event, A Community Q&A on HIV Cure with Bob Siliciano, and building our CAB governance/work plan, among others. 

Please RSVP and join us!

2012 POZ 100 Recognizes defeatHIV Investigators

2012 POZ 100 magazine cover

POZ, December 2012, The POZ 100


The influential HIV advocacy magazine POZ has released its 2012 POZ 100 list, which it devoted to individuals who are “Accelerating the end of AIDS”, and all three Martin Delaney Collaboratories are represented – defeatHIV, CARE and DARE.  Read below for their recognition of our defeatHIV investigators.

While there is still much work to be done in our pursuit of a cure, we are making progress and are excited about the re-energized focus on HIV cure efforts.  We thank POZ and the NIAID/NIH, through their Martin Delaney Collaboratory funding, for continuing to support our vital research.

From POZ

“From scientists and researchers making groundbreaking discoveries to the advocates and politicians on the front lines of the epidemic, this year’s list recognizes people who have made a significant contribution to speeding up the end of AIDS.  Through their efforts, the cure might be closer than you think.”

Keith Jerome, MD, PhD and Hans-Peter Kiem, MD

“Both of the Fred Hutchinson Cancer Research Center in Seattle, Jerome and Kiem are developing proteins known as endonucleases to target HIV.  They’re also collaborating with Sangamo BioSciences to further study the use of gene therapies to render the immune system resistant to the virus.”

Tae-Wook Chun, PhD

“A scientist at the National Institute of Allergy and Infectious Diseases, Chun and his colleagues were among the first to find HIV reservoirs, those long-lived, HIV-infected CD4 cells impervious to ARVs. That was in 1997; since then, he’s been heavily involved in researching was to eradicate them.”

Jim Mullins, PhD

“The professor of microbiology, medicine and laboratory medicine at the University of Washington is working to find an HIV vaccine.  He leads one of the two labs that did genetic analysis of the virus in the RV144 vaccine trial in Thailand, which showed some protection against HIV.”

Ann Woolfrey, MD

“A pediatric oncologist at Seattle Children’s Hospital, she specializes in bone-marrow transplants. She’s the lead investigator for many clinical trials of the Seattle Cancer Care Alliance, including a trial of a mechanism similar to one that cured Timothy Brown of HIV.”


[clear]
Excerpts from POZ issue #184, published December 2012: The POZ 100 – Accelerating the End of AIDS