A Gene Therapy Revolution?

New amfAR gene therapy grants awarded as FDA panel recommends approval of first ever gene therapy-based treatment in the U.S.

On July 12, a Food and Drug Administration panel for the first time recommended approval in the U.S. of a gene therapy-based treatment. The treatment, first developed by Dr. Carl June of the University of Pennsylvania, a member of amfAR’s Cure Council, is based on the use of so-called CAR cells to kill cancer cells.  

On July 13, amfAR announced two new grants to research teams pursuing similar strategies involving CAR (chimeric antigen receptor) cells, which have shown significant potential for their ability to kill HIV-infected cells. The grants are part of a new round of seven awards totaling $2.3 million in support of gene therapy-based approaches to curing HIV.  They were awarded through the amfAR Research Consortium on HIV Eradication (ARCHE), a program that fosters collaboration among teams of scientists. 

“Curing HIV is no longer a pipe dream, and the case of ‘the Berlin patient’ provides proof-of-principle that a cure is possible. However, several complex scientific challenges remain, and these new grants reflect amfAR’s determination to pursue a range of strategies to overcome them.”

CAR Cells and Cure

Scott Kitchen, Ph.D., of University of California, Los Angeles, plans to improve the effectiveness of CAR cells at killing HIV-infected cells by increasing their ability to detect the appropriate target cells and prolonging their survival. He also plans to engineer improvements to minimize the loss of CAR cells to attack by the immune system, and to design a mechanism to “switch off” CAR cells should they become unsafe or are no longer needed.

And a team led by Richard Wyatt, Ph.D., of The Scripps Research Institute in La Jolla, CA, plans to generate CAR T cells with the ability to kill HIV-infected cells just as they begin to produce virus. Additionally, the CAR T cells will be engineered to produce antibodies that may destroy virus and the cells that produce it.

The other grantees are: Hildegard Büning, Ph.D., of Hannover Medical School in Hannover, Germany; Keith Jerome, M.D., Ph.D., of University of Washington in Seattle; Hans-Peter Kiem, M.D., F.A.C.P., of Fred Hutchinson Cancer Research Center, Seattle; Yasuhiro Takeuchi, Ph.D., of University College London, United Kingdom; Drew Weismann, M.D., Ph.D., of University of Pennsylvania, Philadelphia.

Genetic Scissors 

The researchers will pursue projects aimed at: designing and refining vectors that can accurately target the cells that make up the reservoir and regions such as the lymph nodes, where the reservoir cells tend to be concentrated; and exploring the potential of using viral and non-viral delivery mechanisms to deliver emerging types of genetic scissors that could cut the virus out of human DNA.

“Curing HIV is no longer a pipe dream, and the case of ‘the Berlin patient’ provides proof-of-principle that a cure is possible,” said amfAR Chief Executive Officer Kevin Robert Frost, referring to the only person known to have been cured of HIV. “However, several complex scientific challenges remain, and these new grants reflect amfAR’s determination to pursue a range of strategies to overcome them.” 

New Innovation Grants

In a second round of grants, amfAR awarded $1.2 million to six researchers who will explore mechanisms of HIV persistence and the potential for HIV eradication. These “Innovation” grants are designed to test and advance innovative ideas in the early stages of testing.

“Through these projects, we will continue to forge the scientific alliances − within HIV and beyond − that we believe are our best hope for accelerating progress toward a cure.”

For instance, Andrew Badley, M.D., from the Mayo Clinic College of Medicine in Rochester, MN, will test whether ixazomib, a drug currently used to treat the blood cancer multiple myeloma, can reduce the size of the viral reservoir in the body. Joshua Schiffer, M.D., from Fred Hutchinson Cancer Research Center in Seattle, WA, will test a drug normally used to prevent organ transplant rejection for its potential to eliminate the persistent HIV reservoir.

Andrew Henderson, M.D., from Boston University School of Medicine in Boston, MA, and Fabio Romerio, Ph.D., from University of Maryland, Baltimore, MD, will both explore a cure strategy known as “block & lock,” which aims to permanently silence HIV and prevent the emergence of virus when antiretroviral therapy is stopped.

Brad Jones, Ph.D., from The George Washington University, Washington, DC, aims to develop a new class of broadly neutralizing antibodies that enable the immune system to recognize proteins not normally accessible to the body’s antibody making machinery. The goal is to increase the number of people in whom broadly neutralizing antibodies are able to find and kill HIV-infected cells.

Berlin Patient

And to better understand how Timothy Brown, “the Berlin patient,” was cured of HIV, Benjamin Burwitz, Ph.D., from Oregon Health and Science University in Portland, will explore the precise mechanisms that led to his cure by generating a monkey model lacking the protein CCR5, the primary means by which most types of HIV infect cells.

“These two rounds of grants get to the heart of the scientific challenges we face in our search for a cure,” said Dr. Rowena Johnston, amfAR’s vice president of research. “Through these projects, we will continue to forge the scientific alliances − within HIV and beyond − that we believe are our best hope for accelerating progress toward a cure.” 

Learn more about the ARCHE and Innovation grants.

• Press Release: New amfAR Research Grants Advance Gene Therapy and Other Innovative Approaches to HIV Cure

Shocking Latent HIV, Enhancing Immune Defense with a Single Drug

Last month we highlighted the work of scientists from the amfAR Institute for HIV Cure Research at the University of California, San Francisco, and their identification of a new pathway to induce HIV out of its latent state. Such activation renders the virus vulnerable to attack by the immune system. Unfortunately, many of the drugs currently being studied as such latency reversing agents work much better in the test tube than in patients.

Dr. Ole Søgaard

Writing in the June issue of the journal Clinical Infectious Diseases, amfAR-funded scientist Dr. Ole Søgaard of Aarhus University in Denmark, with colleagues from there and the University of Copenhagen, joining an international team from Barcelona, Berlin, Belgium, Boston, San Francisco, and Philadelphia, report on an experimental drug with the capacity not only to activate latent HIV, but also to enhance the patient’s innate immune defenses against the activated virus.

Lefitolimod, also known as MGN1703, activates a protein known as TLR9, found on the surface of many types of immune cells. It belongs to a class of agents known as “immune surveillance reactivators,” which induce production of immune hormones, such as interferon-alpha, and enhance the function of dendritic cells, B cells, and natural killer cells. All of these cell types form part of our innate defense against HIV. Lefitolimod is currently in advanced stages of testing in colon cancer patients.

Based on promising studies in the test tube with cells from HIV-infected patients, Søgaard and associates sought to test the drug’s effects in patients themselves.

Fifteen adults taking effective antiretroviral therapy (ART) for at least one year were enrolled in the study. Lefitolimod was injected under the skin twice a week for four weeks. In 40% of the participants, HIV levels dramatically increased, from undetectable (less than 20 copies) to over 1500 copies, consistent with the role of a latency reversing agent. In addition, the researchers observed an enhancement of all immune responses evaluated.

The authors noted that the use of another drug to enhance TLR7, a related immune surveillance reactivator, in monkeys infected with the simian form of HIV also showed promising results, but only when combined with a therapeutic vaccine.

They concluded that their research is “the first clinical trial using a single drug in HIV-1-infected individuals on ART with the aim of both enhancing innate immunity and activating the HIV-1 reservoir.”

Further studies are underway in this promising area of cure research.

Dr. Laurence is amfAR’s senior scientific consultant.

Gene-Editing Tool Reduces HIV in Infected Mice

Dr. Marcella Flores, associate director of research at amfAR

Researchers at Temple University and the University of Pittsburgh have been able to cut a fraction of HIV out of infected mice using CRISPR gene-editing technology, according to a new study in Molecular Therapy. The study builds upon previous findings by the research team, including one where CRISPR was used to cut HIV out of transgenic mice (genetically modified mice with HIV DNA inserted into their genomes—as opposed to having been infected with HIV).

In this study, researchers reduced HIV RNA (a measure of HIV) in transgenic mice by 60−95%. They were able to achieve a 96% reduction when they used the method in mice with EcoHIV, a mouse equivalent of HIV, during acute infection.

Employing a more widely used humanized BLT (bone marrow, liver, and thymus) mouse model, the researchers found that CRISPR was able to cut a fraction of HIV out of latently infected cells in some organs.

“It’s a good step forward,” said Dr. Marcella Flores, amfAR’s associate director of research. “It would be important to repeat the studies in monkeys and ensure that CRISPR is able to excise HIV from reservoir cells.”

Read more about the study here: http://bit.ly/gene-editing-tool

Using Mice to Detect 'Undetectable' HIV

A major part of amfAR’s “Countdown to a Cure for AIDS” initiative, which is aimed at developing the scientific foundations for a cure by 2020, is to determine the best method to detect and measure latently infected cells from individuals on antiretroviral therapy (ART).

Dr. Ramesh Akkina

This is critical to assessing the outcome of a cure intervention. Writing in the April issue of the journal Virology, amfAR-funded scientist Dr. Ramesh Akkina and colleagues at Colorado State University, along with researchers from the amfAR Institute for HIV Cure Research and Harvard University, reported a very novel approach.

The current “gold standard” for detecting persistent HIV is a test-tube technique known as qVOA (quantitative viral outgrowth assay). It is cumbersome and involves chemicals and antibodies in an attempt to activate virus in latently infected cells. One of its greatest drawbacks, however, is its inability to detect every virus that is capable of growing out of infected cells, estimated at approximately 60 per million cells. Akkina and colleagues sought a living alternative, using mice with human immune systems.

To “humanize” the mice and thus enable HIV to grow in these animals, the researchers used genetically immune-deficient mice transplanted with human stem cells or with bone marrow, liver, and thymus gland cells. They injected these animals with varying numbers of CD4+ T cells—from 100,000 to 20 million cells per mouse—obtained from 11 HIV-positive donors, all on ART. Five of these donors had undetectable viral loads by the standard qVOA.

The injected mice were followed for eight weeks. At weekly intervals blood was obtained in an attempt to detect, by a very sensitive molecular test known as RT-PCR, virus that wasn’t detectable using qVOA. Of the five qVOA-negative samples, four proved positive in the mice. The one sample that failed to produce virus was said to be of “poor quality”—donor samples had been frozen and don’t always thaw out well.

The authors concluded that the higher sensitivity of their humanized mouse models over qVOA and other types of mice used in similar experiments may ultimately lead to avoiding ART interruption as the only means to definitively assess the effectiveness of a potential HIV cure.

Let the mice do the work.

Dr. Laurence is amfAR’s senior scientific consultant.

Lab Mice Photo By Maggie Bartlett, NHGRI. - http://www.genome.gov/pressDisplay.cfm?photoID=5006, Public Domain, https://commons.wikimedia.org/w/index.php?curid=19805359