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Early New Stem Cell Research in HIV+ with lymphoma given new hope: see interview below
  "The stem cells were introduced into these mice. The stem cells will then go to the thymus, develop into mature, functional T-cells - we call these CD8 T-cells because those are the killer T-cells we want......I will say it would take several years to develop an additional library of T-cell receptors, a few more years to test it pre-clinically, and then we'd have to go to clinical trials, we're talking about 10 years before it can be used commercially if it was to work.....stem cells, once they're isolated, would be manipulated in the lab to put the gene of choice in. It would then be re-infused probably intravenously back into the patient"
June 18, 2010 by Lin Edwards
( -- The Human Immunodeficiency Virus (HIV) is widely treated using highly active antiretroviral therapy (HAART), which patients must continue throughout their lives. Now a new study suggests the patients' own stem cells could be genetically modified and then transplanted back into their bodies to give them a single administration therapy, given once and lasting for life. This could avoid the costs and the toxic side effects of the traditional HAART.
Gene therapy had been investigated before but the new genetic material lasted only a few months to a year. The new research, carried out by a team led by John Rossi, a molecular geneticist from the City of Hope cancer center in Duarte, California, has found the new genetic material was still in the blood up to two years after the transplants.
The research results follow a report last year of the "Berlin patient," who received a stem cell transplant to treat leukemia. The transplant came from the bone marrow of a donor who was found to have a mutation in the CCR5 gene, which codes for a receptor that allows HIV to enter immune cells. After the transplant the patient appeared to be completely cured of the leukemia and of AIDS, which makes it the only known case of AIDS being cured. It is not certain that the mutation caused the cure, but it seems likely.
The proof-of-principle research was carried out on four HIV patients who needed bone marrow transplants because of a blood cancer called AIDS-related lymphoma. As part of the normal treatment, the patients' bone marrow was removed and they then received chemotherapy to destroy the cancer cells in the remaining marrow and blood system. Blood stem cells were extracted from the marrow.
Ordinarily, the stem cells would be transplanted back after the chemotherapy, but in the experiment the researchers genetically manipulated a small number of them, inserting three therapeutic genes, including one that cripples CCR5, before returning the cells to the patients. Dr Rossi said the combination of three genes was intended to increase the effectiveness since it would make it more difficult for the virus to escape, but as a safety precaution they did not implant a large number of cells.
The number of cells expressing the modified genes was too low to provide a therapeutic benefit, but the research did prove the principle that genetic manipulation of stem cells may be a valuable way of treating patients with HIV and AIDS in the future without having to find rare donors who already have a beneficial genetic mutation. The research found no evidence of adverse effects for any of the patients and all four are still free of lymphoma two years after the treatment.
Dr Rossi said the next step is to determine the proportion of stem cells that need to be modified for each patient. Animal studies may provide some answers, but eventually, "if done right," genetic therapy could replace daily antiretroviral therapy. The current therapy is effective and allows patients to live relatively normal lives, but it is financially out of reach for millions of patients in developing countries, and has side effects that can still shorten patients' lives.
Rossi's team are also working on ways to make the transplant procedure less risky and toxic, to enable it to be used for HIV patients who do not have cancer.
The City of Hope research institute is a non-profit organization based near Los Angeles. The results of the research were published in the journal Science Translational Medicine.
More information: RNA-Based Gene Therapy for HIV with Lentiviral Vector-Modified CD34+ Cells in Patients Undergoing Transplantation for AIDS-Related Lymphoma, Sci Transl Med 16 June 2010: Vol. 2, Issue 36, p. 36ra43, DOI:10.1126/scitranslmed.3000931
Can Your Stem Cells Kill HIV?
Full Interview Transcript POSTED: Friday, June 18, 2010
Jerome Zack, Ph.D., Professor of Microbiology, talks about using stem cell injections to treat HIV...
How do the blood stem cells you created work?
Dr. Jerome Zack: The idea behind the recent work was to engineer blood stem cells so that they would develop into lymphocytes, which are a mature blood cell type that can kill HIV.
Are those what T-cells are?
Dr. Zack: T-cells, yes. There are two types of T-cells - CD4 and CD8 cells. CD4 cells are the ones that get infected; CD8 cells are the ones that kill infected cells and stop virus replication. What we're doing is engineering the stem cell to become a CD8 killer cell that could actually kill HIV infected T-cells.
How would you do that?
Dr. Zack: We have a gene for a receptor - a surface molecule on the T-cell - called a T-cell receptor, which we could introduce into the stem cell. We then model that by putting the stem cell into an organ called the thymus, which is actually found above your heart, and that is where T-cells develop from stem cells. When we put it through the thymus, that developed T-cells for us. They expressed the receptor that we had cloned into them and they were able to kill HIV target cells.
Do HIV patients lack these T-cells?
Dr. Zack: HIV patients' immune systems are severely compromised. They may indeed be lacking functional T-cells to stop the virus. Often times, their immune systems are exhausted. The thought would be, if you could replenish their immune systems with new functional T-cells, you might be able to calm down the virus.
Have you done this in mice?
Dr. Zack: We've done this using human cells put through mice, and the mice were used as a culture vessel, if you will, to hold a human thymus. This whole strategy has to be done with the human thymus tissue there or the cells won't develop, so we used mice that were engineered to have a human thymus within them.
What happened to the mice?
Dr. Zack: The stem cells were introduced into these mice. The stem cells will then go to the thymus, develop into mature, functional T-cells - we call these CD8 T-cells because those are the killer T-cells we want. We took the cells out and showed that they could kill HIV infected cells in the laboratory.
What's your next step?
Dr. Zack: The next step would be to use a more robust model to show that we can actually do this - completely show HIV infection, as well as HIV killing within the animal model like a mouse. It would be a more advanced mouse system than we use right now. Subsequently would be clinical trials, but prior to that, there's one caveat - HIV has a very, very fast mutation rate, so using one T-cell receptor would not be efficacious. One would have to have a library of T-cell receptors specific for pieces on HIV, so we would have to develop a larger library of T-cell receptors before this could be used clinically.
How long will it take before we you see that?
Dr. Zack: Putting a timeframe on HIV diseases is always a loaded question because every time we've tried to answer that question about any aspect of the disease, we've been wrong. I will say it would take several years to develop an additional library of T-cell receptors, a few more years to test it pre-clinically, and then we'd have to go to clinical trials. Clinical trials will often take, if successful, even seven years before it would go to actually be FDA approved, so we're talking about 10 years before it can be used commercially if it was to work.
Is this a possible genetic vaccine?
Dr. Zack: Yes, so what we're really doing is engineering the immune system using genetic engineering to respond to a foreign particle of choice, in this case, the AIDS virus. Basically, with our technology, we've shown proof of principle that you can engineer the immune system in humans to fight whatever infection you'd like, so we're now also moving forward towards using this technique to fight cancer or other viral infections.
The whole field of stem cell research is booming. What we are using is adult stem cells or blood forming stem cells. The field of embryonic stem cells is also booming and we're involving that as well, although this current work did not use embryonic stem cells, but clearly, for regenerative medicine, for fighting many diseases, including infectious diseases like we're proposing, stem cells really are, in my opinion, the way of the future.
Where would you get the stem cells to treat an individual?
Dr. Zack: In our particular case, these were bone marrow derived stem cells from the same individual. There are ways to fairly easily make those cells leave the bone marrow and go into the peripheral blood, and then clinicians can isolate those stem cells. You would just treat them in a laboratory like we did in our experimental system and then re-infuse them back into the patient. This type of gene therapy trial has been tested many times. It's very similar to a bone marrow transplant.
Would it be given as an IV?
Dr. Zack: Yes, the stem cells, once they're isolated, would be manipulated in the lab to put the gene of choice in. It would then be re-infused probably intravenously back into the patient. What they would then do is go back to the bone marrow where they came from and further develop, and then the cells that came from them would move to the thymus and become T-cells.
Would this not only fight HIV, but also prevent it?
Dr. Zack: This could be used to prevent, but I would argue that it would not be the most efficacious use of the strategy because it's labor intensive, and at this point, fairly expensive. Really, for pre-exposure vaccination, which is what you're referring to, a standard vaccine would be the way to go. An efficacious standard vaccine hasn't even been developed yet, so our therapeutic would be used really as post-exposure treatment, so really, someone who's already infected would be the most obvious choice, although one could develop this for pre-infection.
Is there currently a cure?
Dr. Zack: There is no cure for HIV disease.
Would this cure it or would it just continue to keep your body fighting?
Dr. Zack: When optimized, this would certainly improve the immune response to hold the virus in check. Whether it would cure or not, one can't say. Cure is a scary word in the HIV field because it hasn't been affected yet. It would be nice if it could be cured, but that's setting the bar a little high. I think if we can control infection, if you can keep the amount of virus down, you decrease transmission, you decrease disease progression so the patient feels better and they won't transmit the virus to other people as easily.
How long ago did you start your research into AIDS and HIV?
Dr. Zack: I started working on AIDS and HIV in 1987.
How will this make people with HIV and AIDS lives different than it already is now?
Dr. Zack: The standard regimen that people use to treat HIV disease consists of a cocktail of pharmacologic drugs, medications, if you will, that are very effective at controlling virus replication. You can bring virus replication down to undetectable levels in many patients and they'll stay that way for years. The disadvantage is the drugs themselves are toxic, and also, they can create resistance. In the case where a patient cannot take drugs any longer because of toxicities or breakthrough because of virus resistance against the drug, you would need a genetic therapy such as this. In addition, the drugs are expensive and I know many HIV patients that would really prefer to be off of their medication, so there's excitement if this approach would work. In theory, it would allow them to go off of pharmacologic drugs and should have fewer side effects compared to the current therapy regimen.
Would a patient need a stem cell injection every five years or is it a one-time treatment?
Dr. Zack: In theory, since a stem cell lives the life of the individual, one treatment, if optimized - and if this was to work in clinical trials - could, in theory, produce a lifelong effect. In practice, it may take more than one, but I imagine it would be few treatments and not many treatments. If this was to be successful in clinical trials, and as technology improves, I would envision it to be a relatively non-burdensome approach to keep virus load in check.
How did the T-cells change in the mice?
Dr. Zack: It's a tricky question. Mice actually can't be infected with HIV, which is the reason why we transplant human cells into them. We've been spending the last 20 years working with these mouse models where we transplant human tissues to find out how HIV replicates in the human tissues. I don't think I can actually directly answer your question because the mice themselves don't get infected, just the human tissue.
In your studies without mice, how much did it increase T-cells?
Dr. Zack: I don't have that information, but you asked me what the next step was. The next step is to set up the model where we can both put in HIV to get infection and then put in the stem cell strategy to show that the strategy is efficacious in the body. That's our next step. We don't have that model working just yet. We envision it will be working in the next few months and then we can do that test.
Is there any risk to this type of stem cell treatment?
Dr. Zack: There is always a risk to any kind of a new approach. I suppose one risk to this would be we would be obtaining stem cells from the infected individual. Those would be taken out of the body and then re-implanted. If the re-implantation didn't work, the patient would be shy the number of stem cells that we took out. Because we're not taking all the stem cells out, it was thought that it wouldn't be a problem, but it might presumably be problematic at some point.
How would it be problematic?
Dr. Zack: That's a great question. Bone marrow derived stem cells make all the cells found in the blood, which include red blood cells which carry oxygen, and the various forms of white blood cells that fight bacteria and fight disease and kill viruses. Without any stem cells, you wouldn't have the immune system or a blood system. We would be taking out a small fraction of those stem cells, genetically engineering those, and then replacing them back into the body. With the off chance that the stem cells were not returned, the individual would have fewer stem cells in their bone marrow, but it would be a small proportion of their normal component of stem cells, so I doubt it would have a major impact clinically.
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