The only cures of CLL have been with stem cell allografts. Whereas in the past we thought that this was another way of directing massive doses of chemotherapy or radiotherapy at the bone marrow and being able to rescue the normal cells with a transplant from someone else, we now know that the benefit comes from the transplanted cells not the chemotherapy. Chemotherapy (or radiotherapy) is only needed to allow the transplant to take place and its main characteristic is to be immunosuppressive rather than myeloablative. So immunosuppressive drugs like fludarabine and alemtuzumab are more important than myeloablative drugs like melphalan or busulphan, and the dose of Total Body Irradiation needed is more like 2 Gray than 12 Gray.
The transplant works by what is called Graft-Versus-Leukemia (GVL). The problem with this approach to cure is that it is mixed up with a Graft-Versus-Host (GVH) effect which is capable in the worst circumstances of killing the recipient and if not, of conveying a very unpleasant and hard-to-treat disease.
The GVL effect works through the graft's T-cells which are directed at minor differences between the histocompatability antigens of the graft and host. We often don't know what they are or even if there are any.
For some time several scientists (including my own daughter) have been working at re-educating T cells so that they will attack specific tumor targets. Today's breakthrough presents a successful way of doing this. I first came across this particular approach when I received the papers for a Gene Therapy Meeting in January this year, and I was very enthusiastic about it, although I could not do more than hint at its promise then. Gene therapy has reached a greater maturity in the 10 years that I have been attending GTAC meetings and for the most part now it is very safe. Although it makes use of retroviruses like HIV to transfer genes into different cells, the HIV has been thoroughly gutted of all the harmful ingredients and as I demonstrated earlier in the year, there have been sone remarkable successes.
With the use of gene-transfer techniques, T cells can be genetically modified to stably express immunoglobulin molecules (antibodies) on their surface, conferring new antigen specificity. Chimeras were mythological animals that consisted of part one animal, part another. An example would be a Centaur with a man's head and chest and horse's body or a mermaid with a woman's top and a fish's tail. We now use the term to describe a mixed molecule from different cells.
Chimeric antigen receptors combine an antigen-recognition domain of a specific antibody with an intracellular domain of the CD3-zeta chain or FcγRI protein into a single chimeric protein. Although chimeric antigen receptors can trigger T-cell activation in a manner similar to that of normal T-cell receptors, a major barrier to the clinical application of this technique to date has been not having enough cells to attack the tumor. It has not been possible to expand the numbers of these cells inside the patient resulting in disappointing clinical activity.
The activity of chimeric antigen receptor–mediated T-cell responses can be further enhanced with the addition of a costimulatory domain. In preclinical models, these scientists found that inclusion of the CD137 (4-1BB) signaling domain significantly increased antitumor activity and the persistence of chimeric antigen receptors in the patient compared with inclusion of the CD3-zeta chain alone.
In most cancers, tumor-specific antigens for targeting are not well defined, but in B-cell neoplasms, CD19 is an attractive target. Expression of CD19 is restricted to normal and malignant B cells and B-cell precursors. The authors of the report in the New England Journal of Medicine have begun a pilot clinical trial of treatment with autologous T-cells expressing an anti-CD19 chimeric antigen receptor (CART19); three patients have been treated. In my next blog I will give details of what they have done.