Sunday, October 16, 2011
A chimeric virus to cure leukemia? Yes, we can!
Last week I talked about gene therapy and vaccines targeting tumor cells. Following those posts, a friend of mine (thanks, Alex!) pointed me to a recent case report published in the New England Journal of Medicine, which describes a successful use of gene therapy to treat leukemia . Since you know I like to talk about chimeric viruses and all the wonderful things you can do with them, I was instantly drawn to the paper.
Leukemia is a type of cancer that causes an abnormal increase in white blood cells. The patient discussed in the NEJM case report was affected by a type of leukemia called B-cell neoplasm, which, as the name indicates, causes the abnormal proliferation of B-cells.
So, how do you address the problem using gene therapy?
This is what we need: (a) a target on the tumor cells that will tell the immune system to destroy them; (b) a weapon for the immune system to recognize and kill the tumor cells; (c) a way to "give" the weapon to the immune system.
The answer to (a) comes from a receptor called CD19, which is expressed by malignant B-cells. The "weapon" (b) is a genetically engineered anti-CD19 antigen receptor, which enables T-cells (our immune system "soldiers") to recognize the malignant B-cells and destroy it. The big question is (c): how do we make T-cells with the anti-CD19 antigen receptor?
This is where gene therapy and chimeric viruses come into play. How do we use gene therapy to transfer the genes that express the anti CD19 antigen receptor into the T-cells? We need "something" that does this for a living -- transfer genes into cells. Remember what that is?
Absolutely, a virus.
Now, remember what virus in particular targets T-cells?
HIV, of course!
And that's exactly what the authors of this study did: they created an HIV chimeric virus and endowed it with the genes of the anti-CD19 antigen receptor. T-cells were collected from the patient, transduced (which means that the genetic material was transferred inside the T-cells using the modified HIV virus), then infused back into the patient.
Like in all best stories, at first things seemed to go terribly wrong: two weeks after the transfusion, the patient started having high fevers; three weeks after treatment the patient had to be hospitalized and treated for metabolic complications consistent with leukemia treatment.
And then the miracle. One month after the infusion there were no more tumor cells in the patient's blood. At the time the paper was written -- ten months after the therapy -- the patient was still in remission, and the antigen recognizing T-cells were still proliferating.
Interestingly, this case report reminds of an almost symmetric case reported in 2008: an HIV-positive patient who developed leukemia was treated with a bone marrow transplant from a donor who had the Delta32 CCR5 mutation I discussed in this post. The mutation modifies T-cells in a way that they can no longer be infected by the HIV virus and, indeed, after the bone marrow transplant, the patient's viral load dropped and never recovered. As far as I know, the patient is the only one ever to be cured of AIDS.
 Porter, D., Levine, B., Kalos, M., Bagg, A., & June, C. (2011). Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia New England Journal of Medicine, 365 (8), 725-733 DOI: 10.1056/NEJMoa1103849