For the first application of the new vector five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were given a single infusion of their own immune cells that had been genetically modified for HIV resistance.
The researchers, led by Carl June, MD, and Bruce Levine, PhD, of the Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, along with Rob Roy MacGregor, MD, Professor of Medicine, report their findings in the online edition of the Proceedings of the National Academy of Sciences. Viral loads of the patients remained stable or decreased during the study, and one subject showed a sustained decrease in viral load. T-cell counts remained steady or increased in four patients during the nine-month trial. Additionally, in four patients, immune function specific to HIV improved.
Overall, the study results are significant, say the researchers, because it is the first demonstration of safety in humans for a lentiviral vector (of which HIV is an example) for any disease. Additionally, the vector, called VRX496, produced encouraging results in some patients where other treatments have failed.
"The goal of this phase I trial was safety and feasibility and the results established that," says June. "But the results also hint at something much more."
Each patient received one infusion of his or her own gene-modified T cells. The target dose was 10 billion cells, which is about 2 to 10 percent of the number of T cells in an average person. The T-cell count was unchanged early after the infusions. "We were able to detect the gene-modified cells for months, and in one or two patients, a year or more later," says Levine. "That's significant – showing that these cells just don't die inside the patient. The really interesting part of the study came when we saw a significant decrease in viral load in two patients, and in one patient, a very dramatic decrease.
But, cautions Levine, "just because this has produced encouraging results in one or two patients doesn't mean it will work for everyone. We have much more work to do." In the current study, each patient will be followed for 15 years.
"The new vector is a lab-modified HIV that has been disabled to allow it to function as a Trojan horse, carrying a gene that prevents new infectious HIV from being produced," says Levine. "Essentially, the vector puts a wrench in the HIV replication process." Instead of chemical- or protein-based HIV replication blockers, this approach is genetic and uses a disabled AIDS virus to carry an anti-HIV genetic payload. The modified AIDS virus is added to immune cells that have been removed from the patients' blood by apheresis, purified, genetically modified, and expanded by a process June and Levine developed. The modified immune cells are then returned to the patients' body by simple intravenous infusion.
This approach enables patients' own T cells, which are targets for HIV, to inhibit HIV replication – via the HIV vector and its anti-viral cargo. The HIV vector delivers an antisense RNA molecule that is the mirror image of an HIV gene called envelope to the T cells. When the modified T cells are given back to the patient, the antisense gene is permanently integrated into the cellular DNA. When the virus starts to replicate inside the host cell, the antisense gene prevents translation of the full-length HIV envelope gene, thereby shutting down HIV replication by preventing it from making essential building blocks for progeny virus. VRX496 was designed and produced by the Gaithersburg, Md. biotech company VIRxSYS Corp.
A New Field
The new vector is based on a lentivirus, a subgroup of the well-known retroviruses. The study and its safety profile to date have now opened up the field of lentiviral vectors, which have potential advantages over other viral vectors currently being studied because they infect T cells better than adenoviruses, a commonly used viral vector. Lentiviruses also infect non-dividing or slowly dividing cells, which improves delivery to cells such as neurons or stem cells, thus enabling the evaluation of gene therapy in an even wider array of diseases than before. Furthermore, lentiviral vectors insert into cellular DNA in such a way that may be safer than other gene therapy vectors. This is because lentiviruses appear to insert differently from other retroviruses that have caused side effects in other trials involving stem-cell therapy. In addition, gene insertion by lentiviral vectors is attractive for potential therapeutics since it enables long-term gene expression, unlike other viral vectors where expression is lost over time.
Penn researchers are now recruiting for a second trial using the VRX496 vector with HIV patients whose virus is well controlled by existing anti-retroviral drugs, a group of patients who are generally healthier and have more treatment options available. This trial will use six infusions rather than one and is designed to evaluate the safety of multiple infusions and to test the effect of infusions on the patients' ability to control HIV after removal of their anti-retroviral drugs. The hope is that this treatment approach may ultimately allow patients to stay off antiretroviral drugs for an extensive period, which are known to have significant toxicity, especially after long-term use.
Karen Kreeger | EurekAlert!
At last, butterflies get a bigger, better evolutionary tree
16.02.2018 | Florida Museum of Natural History
New treatment strategies for chronic kidney disease from the animal kingdom
16.02.2018 | Veterinärmedizinische Universität Wien
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).
Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
16.02.2018 | Information Technology
16.02.2018 | Health and Medicine
16.02.2018 | Physics and Astronomy