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:
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.”
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.
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.”
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.”
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 former staff writer at Fred Hutchinson Cancer Research 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.