Rare resistance mechanism against CAR T cell therapy discovered

A rare mechanism through which a patient’s leukemia developed resistance to CAR T cell gene therapy is described in a case report published online this week in Nature Medicine. The phenomenon, which is related to the manufacturing process of CAR T cells, illustrates the need for improved protocols that prohibit such developments.

CAR T cell therapy is a form of personalized medicine in which the immune system’s T cells are isolated from a patient’s blood and engineered to express a so-called chimeric antigen receptor, or CAR, which targets a protein found on the surface of cancer cells. The modified T cells are infused back into the patient’s bloodstream, with the hope of eradicating malignant cells. Last year, CAR T cell therapy for the treatment of children and young adults with incidences of nonresponsive or relapsed B cell leukemia became the first gene therapy approved by the US Food and Drug Administration. Although patients treated with this approach in the clinic have experienced unprecedentedly high remission rates, tumor cells can develop ways to evade the killing capacity of CAR T cells by suppressing the expression of the targeted protein.

Carl June and colleagues describe a novel, exceptionally rare mechanism of resistance to CAR T cells that developed in a patient with leukemia during treatment. In the processing of the T cells, a single contaminating leukemia cell was inadvertently engineered with the CAR and infused back into the patient. This caused the leukemia cell to be effectively masked from the CAR T cells, paving the way for its uncontrolled expansion and the patient’s relapse.

The authors note that this relapse mechanism has not been seen in any of the 369 reported patients worldwide that have been treated with this therapy - and it should be considered an isolated case. However, these findings illustrate the need for improved protocols that can purge contaminating tumor cells, prohibiting detrimental effects.

doi:10.1038/s41591-018-0201-9

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