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January 7, 2014
Adoptive T-Cell Therapy for Cancer: The Short Version
If you're looking for a good overview of the modified-T-cell immune therapies for cancer that have been making such headlines recently, this writeup at Nature is for you. It also makes clear that getting this to work across a broader number of tumor types is not going to be a job for the faint of heart. If the antigen that you're training all those T-cells to go after happens to exist somewhere else in the body (other than on the surface of the tumor cells), or if you have some cross-reactivity that you hadn't realized, the patients are going to be in for a very hard time indeed.
Designing effective treatments requires finding cell-surface antigens for T cells to target without damaging normal tissue. This specificity may prove more difficult than researchers initially thought. Many antigens found in cancer are also expressed in normal tissue — HER2, for example, which is the target of the antibody-based therapy trastuzumab (Herceptin), is also expressed in heart cells. Before researchers can make progress, they must understand how extensively each candidate target is expressed in all tissues of the body.
Recent studies have highlighted what can happen when T cells unexpectedly attack normal tissue. In a clinical trial of TCR-engineered T cells, researchers at the US National Cancer Institute were targeting the cancer-specific antigen MAGE-A3 when two of their nine patients slipped into a coma and died. It turns out that the cells also recognized another member of the MAGE-A family that the researchers later discovered is expressed in low levels in brain tissue. Another type of MAGE-A3-specific TCR caused two patients to die from heart failure when the TCR bound to a similar protein, called Titin, which is expressed on heart cells. Adaptimmune, the company based near Oxford, UK, that developed the T-cell receptor, has implemented more extensive safety testing techniques in an attempt to prevent unexpected reactions in the future.
I'm quite excited about this whole field, but there are very strong reasons why it's been tried (so far) almost entirely on people who are near death. The immune system is to be feared.
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