HIV Gene Therapy, Vaccine

http://www.gizmag.com/spanish-hiv-vaccine-90-percent-immune-response/19973/

Researchers at the Spanish Superior Scientific Research Council (CSIC) have successfully completed Phase I human clinical trials of a HIV vaccine that came out with top marks after 90% of volunteers developed an immunological response against the virus. The MVA-B vaccine draws on the natural capabilities of the human immune system and "has proven to be as powerful as any other vaccine currently being studied, or even more", says Mariano Esteban, head researcher from CSIC's National Biotech Centre.

Dr. Mariano Esteban, head researcher from CSIC's National Biotech Centre (Image: CSIC)
Researchers at the Spanish Superior Scientific Research Council (CSIC) have successfully c...
Map illustrating the HIV virus as spread across the globe (Image: CSIC)
Three-dimensional model of a HIV virus particle (Image: CSIC)

The MVA-B vaccine first showed promising signs back in 2008 when clinical trials involving mice and macaque monkeys demonstrated a very high efficiency against Simian immunodeficiency virus (SIV). The recent human trials involved 30 healthy volunteers, where 24 were treated with MVA-B, while the other 6 were treated with a placebo, carried out over a 48 week period.

Development of MVA-B is based on the insertion of four HIV genes in a previously used vaccine (MVA) for smallpox. When injected with the vaccine, a healthy immune system can react against the MVA, whilst the HIV genes are incapable of self-replicating. This guarantees a safe clinical trial for HIV free volunteers. Furthermore by trialing the vaccine on healthy patients, the immune system can learn how to detect and combat the HIV virus components. "It is like showing a picture of the HIV so that it is able to recognize it if it sees it again in the future", says Esteban.

"Our body is full of lymphocytes, each of them programmed to fight against a different pathogen" continued Esteban. "Training is needed when it involves a pathogen, like the HIV one, which cannot be naturally defeated".

The trial demonstrated how the vaccine stimulates the production of lymphocytes B, which produces HIV attacking antibodies that block the virus from infecting healthy cells. Blood tests during the 48th week revealed that 72.7% of the treated volunteers had developed these HIV fighting antibodies. However generating a long lasting response against future attacks truly renders the vaccine effective. This is achieved when the body maintains a basic memory level of T lymphocytes, which are generated after the first attack and can circulate the body for years. The T lymphocytes are responsible for stimulating the attacked cell's immune response, which can then identify and destroy the HIV virus. Blood tests during the 48th week revealed that the 85% of the patients maintained the memory T lymphocytes immune response.

"MVA-B immune profile meets, initially, the requirements for a promising HIV vaccine," says Esteban. Although it does not remove the virus from the body, the immune response induced by the vaccine could keep the virus under control by destroying the infected cell.

According to CSIC, "if this genetic cocktail passes Phase II and Phase III future clinic trials, and makes it into production, in the future HIV could be compared to herpes virus nowadays".

Phase I clinic trials will also commence with HIV infected volunteers to test its efficiency as a therapeutic vaccine.

Source: Spanish Superior Scientific Research Council (Spanish).

http://news.sciencemag.org/sciencenow/2011/09/gene-therapy-may-thwart-hiv.html?ref=hp


Gene Therapy May Thwart HIV

by Jon Cohen on 19 September 2011, 12:36 PM | 0 Comments

This past year, a Berlin man, Timothy Brown, became world famous as the first—and thus far only—person to apparently have been cured of his HIV infection. Brown's HIV disappeared after he developed leukemia and doctors gave him repeated blood transfusions from a donor who harbored a mutated version of a receptor the virus uses to enter cells. Now, researchers report promising results from two small gene-therapy studies that mimic this strategy, hinting that the field may be moving closer to a cure that works for the masses.

At the Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago, Illinois, this weekend, researchers reported preliminary results from tests of a novel treatment in 15 HIV-infected people designed to free them from the need to take antiretroviral drugs. The studies, conducted separately on the East and West coasts of the United States, attempt to make the immune system resistant to HIV by crippling a receptor, known as CCR5, on T cells that the virus uses during the infection process. The man who donated blood for Timothy Brown's transfusions had naturally defective CCR5 receptors.

The trial participants had T cells removed from their blood and then modified in the laboratory with a designer enzyme engineered by Sangamo BioSciences in Richmond, California. The enzyme, called a zinc finger nuclease, clips the gene for the CCR5 receptor and disables it. Ten billion modified cells were then reinfused into the participants' bodies, and the new data show that about 25% of cells had the mutant CCR5s. The studies found that modified T cells persisted for more than 6 months in several patients.

In one provocative case reported in Chicago yesterday, a patient who received the gene therapy and then stopped taking antiretroviral drugs had HIV return within a month, as typically happens when people interrupt their treatment. But a few weeks later, the virus began to decline, and it dropped to undetectable levels in concert with evidence that the gene therapy had altered his T cells. "Those kinetics are very different from what I've seen in treatment interruption studies, and we've done many," says Pablo Tebas, an infectious disease clinician at the University of Pennsylvania who heads the East Coast study of six participants. "This patient goes down, way down."

Tebas recognizes that his study is uncontrolled and that they've seen this response in only one patient. What's more, the patient already had a natural advantage because he has a crippled CCR5 gene in one of the two copies he inherited. Tebas suspects that the gene therapy coupled with his natural CCR5 mutation combined to lead to the dramatic result. "This is a very small experiment, and I don't think it's a cure by any means, but the Berlin patient is only one patient, and it changed research priorities," Tebas says. "This shows that there's a correlation between antiviral activity and the proportion of modified cells. It shows a path forward."

Although researchers do not expect the gene therapy to entirely clear HIV from the body, they hope it will create a "functional cure"—in other words, contain the virus to such a powerful extent that people no longer need antiretrovirals.

Virologist David Margolis, who is conducting his own HIV cure studies at the University of North Carolina, Chapel Hill, says many questions remain about the impact of this gene therapy, however. "These data are interesting, and encouraging, but still incomplete," he says. Yet Margolis is "impressed" by the percentage of cells that have the artificially modified CCR5 gene.

Even if this gene therapy proves itself, the cost and technical challenge of the intervention means it likely will have little chance of being used outside of wealthy countries. But Tebas notes that the cost of antiretrovirals also is high and that any calculation would have to balance one against the other.


http://www.medpagetoday.com/MeetingCoverage/ICAAC/28595

This report is part of a 12-month Clinical Context series.
By Michael Smith, North American Correspondent, MedPage Today
Published: September 19, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco. Earn CME/CE credit
for reading medical news
Action Points

Note that these studies were published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.


Explain that a gene-based treatment for HIV involving genetically modifying a patient's CD4-positive T cells was safe and well tolerated in two small clinical trials.


Note that the gene therapy resulted in increases in total CD4 counts in both studies.

CHICAGO -- A gene-based treatment for HIV was safe and well tolerated in two small clinical trials, and there are hints that the method is at least a first step toward a so-called "functional cure," researchers said here.

The method involves genetically modifying a patient's CD4-positive T cells -- the target of HIV -- so that they are resistant to the virus, according to Ronald Mitsuyasu, MD, of the University of California Los Angeles, who presented one of the industry-sponsored trials.

"If we can get [patients] to such a level that their own immune system can kick in and control the virus without drugs, that's a win," Mitsuyasu told MedPage Today at the Interscience Conference on Anti-Microbial Agents and Chemotherapy.

In one of the studies, something like that appears to have happened: After an infusion of modified cells, one patient saw his HIV viral load rise and then drop back to undetectable during a planned 12-week drug holiday.

"We never see that in treatment interruptions," Mitsuyasu said.

But the researchers reported that other patients in the study responded to stopped drug therapy with a predictable rise in HIV viral load, followed, in some cases, by a slight decline, but not to the undetectable level of fewer than 50 copies of viral RNA per milliliter of plasma.

The finding illustrates a key challenge, Mitsuyasu told MedPage Today: "We don't know what level of gene modification is adequate" to produce such a robust response, except that it appears to be higher than what they're getting in most patients.

The studies, which involved a total of 15 patients, are mainly looking at the safety of the process, in which CD4 cells are removed from the patient, modified so that they do not express a functional CCR5 receptor, and re-infused.

The CCR5 receptor is the main entry point for HIV, and people with a single genetic variation – the delta-32 mutation in the CCR5 gene – are resistant to HIV. Indeed, those with two copies of the mutated gene are almost immune while those with one copy have a slower disease course.

Mitsuyasu and colleagues are testing whether using genetic techniques to produce CCR5-deficient CD4 cells can lead to HIV treatments and perhaps a "functional cure," in which the patient still carries the virus, but no longer needs drugs to control it and prevent disease.

Several groups are at various stages of trying to modify the gene as a potential therapy, either by altering CD4 cells themselves or by changing blood stem cells. Mitsuyasu and his colleagues appear to be leading the pack at the moment.

In the process they use, Mitsuyasu said, about a third of the modified CD4 cells are "bi-allelic," carrying two modified genes that are nearly immune to HIV in principle. Other cells have a single copy and still others are not affected by the modification.

An Increase in CD4 Cells

Two studies presented here were:

A nine-patient dose-ranging study by Mitsuyasu's team, in which groups of three patients were given 10, 20, or 30 billion modified cells.
A six-patient study that included a 12-week treatment interruption 14 days after a dose of 10 billion cells. This study was led by Dale Ando, MD, at Sangamo Biosciences in Richmond, Calif.

In both studies, there were no serious adverse events, Mitsuyasu said. Most adverse events occurred in the first 24 hours after infusion and were apparently related to the infusion. These adverse events were mild or moderate, and resolved without sequelae.

In the larger study, Mitsuyasu said, patients were on highly active anti-retroviral therapy (HAART) and had an undetectable viral load, but despite a median of 21 years of treatment, they had fewer than 500 CD4 cells per milliliter of plasma.

The researchers found that in all cases the cells appeared to engraft and proliferate, persisting for at least a year both in plasma and in the rectal mucosa, without any apparent dose-response curve. Mitsuyasu also said that:

All patients saw increases in their CD4 cell count, with a median rise in plasma of 163 cells after six months. Not all patients are a year from treatment, but for those who are, the median rise is 100 cells.
The cells can be detected in the rectal mucosa a year after treatment, which demonstrates normal homing to the gut-associated lymphoid tissue, an important HIV reservoir.
The ratio between CD4 and CD8 cells normalized in all patients.

The smaller study enrolled six patients, again all on HAART and without detectable viral loads, but who had more robust immune systems, with a median of 974 CD4 cells per milliliter of plasma.

All were given 10 billion modified cells and 14 days later embarked on a 12-week drug holiday, the researchers reported.

As in the other study, patients saw increases in CD4 cells -- a median increase of 500 cells per milliliter after 150 days -- as well as a normalization of the CD4/CD8 ratio, and persistence of the cells in the blood.

The most striking finding came from the treatment interruption, during which all patients saw an initial HIV viral load increase in the absence of HAART. On the other hand, three patients saw their viral load drop again markedly, including the one whose virus became undetectable.

The patient was one of the people whose CD4 cells already carried one copy of the mutated CCR5 gene; the gene therapy meant that the proportion of re-infused cells carrying two copies was about twice as high as in the other patients.

The researchers said that one implication of their work is that in order to have a similar effect in others, they may need to find ways of increasing the proportion of modified cells that carry two copies of the modified CCR5 gene.

Ongoing Challenges

Indeed, the research probably means the number of modified cells is "more important than previously expected," commented Laurent Kaiser, MD, of the University Hospitals of Geneva, and a member of the conference's program committee.

And that highlights the technical and scientific challenges that still remain before the gene therapy can enter the clinic, Kaiser told MedPage Today.

It's important to remember that gene therapy in various forms has been tried for several years "and still we do not have very many examples where you can use cell-therapy to treat patients." On the other hand, "it's a way to move forward." he said.

The studies were supported by Sangamo Biosciences of Richmond, Calif. Mitsuyasu reported financial links with Sangamo, Janssen Biotechnology, and Merck. Several authors were employees of Sangamo.

Kaiser did not report any conflicts.


Primary source: Interscience Conference on Anti-Microbial Agents and Chemotherapy
Source reference:
Mitsuyasu R, et al "Adoptive transfer of zinc finger nuclease (ZFN) modified autologous CD4 T-cells to aviremic HIV-infected subjects with suboptimal CD4 counts" ICAAC 2011; Abstract H1-375.

Additional source: Interscience Conference on Anti-Microbial Agents and Chemotherapy
Source reference:
Ando D, et al "HAART treatment interruption following adoptive transfer of zinc finger nuclease (ZFN) modified mutologous CD4 T-cells (SB-728-T) to HIV-infected subjects demonstrates durable engraftment and suppression of viral load" ICAAC 2011; Abstract H2-794a.