The second explanation for disease relapse is antigen loss, in which the disease develops therapeutic resistance by losing the target receptor. “The CAR-T cells do everything they’re supposed to do,” explains Dr Fry, “but the leukemia comes back and no longer has the target for the CAR.”

Antigen loss is generally limited to CAR-T therapies and other targeted immunotherapies, such as bispecific T-cell–engager antibody constructs. “With chemotherapy or with sort of less targeted therapies, we have never observed that,” said Marco Ruella, MD, scientific director of the lymphoma program at the University of Pennsylvania, during an interview with Cancer Therapy Advisor. He was not involved in writing the review article.

Antigen loss, Dr Fry asserted, is a “more challenging” cause of relapse and is not limited to ALL or lymphoma. Preclinical evidence suggests antigen loss may occur during treatment of solid tumors, and clinical studies have shown antigen loss can occur during treatment in glioblastoma. “That issue of antigen loss is going to continue to be the bane of our existence,” said Dr Fry.

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“We do need to do something to prevent that or at least to be able to treat those patients,” Dr Ruella stressed, referring to patients who have tumors that have been subject to antigen escape.  As stated in the review article, approaches to antigen loss include designing CAR constructs that target multiple antigens, and several clinical trials are under way to target CD19 and CD22 in ALL ( Identifier: NCT03241940 and NCT03289455), ALL and diffuse large B-cell lymphoma ( Identifier: NCT03233854), ALL and non-Hodgkin lymphoma ( Identifier: NCT03330691 and NCT03448393), and non-Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic leukemia ( Identifier: NCT03019055).

Despite antigen loss being a major challenge, Dr Fry offered an optimistic view: “In some ways it proves that you have effective immunotherapy,” he said. The CAR-T cell therapy, he explained, is “forcing” the cancer to survive in an environment where the antigen is being effectively targeted. “It’s a failure, but it’s a failure that is caused by the success,” he said. “We just have to now figure out how to deal with that.”


  1. Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol. doi: 10.1038/s41571-019-0184-6