The New York Times published an article yesterday that describes a phase 1 study at http://www.nytimes.com/2011/09/13/health/13gene.html?_r=1&pagewanted=all%3Fsrc%3Dtp&smid=fb-share (referring to a study published in the New England Journal of medicine, at http://www.nejm.org/doi/full/10.1056/NEJMoa1103849) that details an attempt to use HIV to transform T cells so they could host target B cells. The host B cells were being targeted because the the three patients had chronic lymphoid leukemia that was no longer responding to chemotherapy nor were they bone marrow candidates.
So, B cells are the problem--now how to get rid of them? These researchers removed billions of T cells from each patient. The best way to transform T cells through gene therapy is to get a really good and specific virus to "infect" it. For T cells, an obvious source is HIV. Researchers made a new version of HIV that lacked the RNA it needed to actually infect a cell but still was able to target T cells and transfer genetic information into them. This new HIV had DNA from mice, humans, cows, and viruses that infect cows and woodchucks in order to disable it. More DNA was added to program the T cells to make a chimeric antigen receptor (CAR) that included three main components: CD19 (for targeting B cells), CD 137 (a costimulatory receptor), and CD3-zeta (for signal transduction). This study is the first time someone has used HIV as a vector for gene therapy in cancer, though it has been done in other studies for different diseases before. Once these new chimeric antigen receptor-modified T cells were made from the original billion or so (and only 15 million for one of the patients) extracted from the patients, they were put back into the subjects. Remarkably, the T cells infused multiplied by 1000 to 10000 times.
After 10 days of relatively nothing happening, one of the patients began to feel an intense fever, shaking, chills, and experienced a sharp decrease in blood pressure. What was happening here? Cytokines, my friend, lots of cytokines. Fighting a tumor that size means tons and tons of cytokines from attacking all the B cells of the body. Luckily, the patient's symptoms resolved within a few weeks, and with that the tumor had also completely disappeared. The doctors estimated that two pounds of cancer cells had been killed off in those few short weeks, and the patient was declared as being in remission.
But, as you can see, a procedure like this one is not without risk. The patient described above survived the barrage of cytokines, but if it was worse the cytokine storm could have killed him. Another possible problem is cross reaction between the chimeric antigen receptor for the target (in this case, B cells) and another antigen on a healthy cell in the body. This happened before to a woman with colon cancer, whose targeted cancer antigen cross-reacted with a protein found on her lungs. She died shortly after. It is also known that many antigens on cancer cells can cross-react with proteins found on basement membranes.
So, overall we have total remission for two patients, partial remission for one, and a host of possibilities and risks. What do you think are other ways we could use this information? What woud you do to reduce the risks associated with this?
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