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A Leukemia Breakthrough? Really? Are “engineered” TCRs the hope?

The New York Times recently reported on a “Breakthrough in the leukemia battle”. A scientific team led by Carl June at the University of Pennsylvania has been trying to “engineer” T lymphocytes (T cells), one of the two major classes of lymphocytes, that normally function to recognize and respond to invasion by foreign microbes, so that they can perform a similar role to rid our bodies of cancer. To do so, the team at UPenn used a virus similar to the Human Immunodeficiency Virus (HIV) to infect T cells from a young girl suffering from Acute Lymphoblastic Leukemia (ALL), to transfer genes coding for a T cell antigen receptor (abbreviated TCR) capable of recognizing a molecule termed CD-19, which is expressed on the surface of B lymphocytes, both normal and leukemic. Then these engineered cells are infused back into the patient, in the hopes that they will seek-out and recognize and react to the CD-19 molecules on the surface of the leukemia cells. Normally, T cells recognize foreign microbes in this way, and when they react, they produce “effector molecules” called cytokines or interleukins, which generate an inflammatory reaction, sometimes as severe as that seen in Toxic Epidermal Necrolysis (TEN). According to the Times’ report, this is exactly what happened to the young leukemia patient. She became so ill that it seemed sure that she would die very soon. Therefore, faced with a situation against the Hippocratic Oath, which teaches “first, do no harm” the physicians tried to rescue her by infusing antibodies reactive with interleukin-6 (IL-6), which is one of the most potent inflammatory molecules. Fortunately, this drastic last-ditch effort worked, and the youngster did not die, but went on to recover, apparently free of her diseased leukemia cells.

There are lessons to be learned from this case, the first is that if T cells express TCRs that are capable of recognizing and reacting with leukemia cells, they can effectively reduce the cancer cells to undetectable levels. Secondly, the ways by which T cells respond to leukemia cells are the same ways that they respond to foreign microbes, i.e. by producing interleukins that can result in severe inflammation, which themselves can be lethal. Essentially these molecules are responsible for “septic shock” seen in severe microbial infections. Thus, although sensational and provocative, I predict that this approach, i.e. of engineering T cells to become anti-cancer cells will not be “the magic bullet” envisioned by immunologists who want to “cure” cancer. However, it may be possible to learn from these human experiments, so that one can use them for therapy without toxicity, which is the challenge for the future.

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