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A decade of discoveries in Cancer Discovery. For the community. By the Community.


Converging on an Escape Route from CAR-T Cell Therapy

Artowork representing the article: Converging on an Escape Route from CAR-T Cell Therapy

One of the major therapeutic advances in cancer research over the past decade has been the development of chimeric antigen receptor (CAR)-T cell therapy, a type of adoptive cell transfer in which a patient’s T cells are collected, engineered to express a receptor targeting a specific tumor antigen, expanded ex vivo, and infused back into the patient. CAR-T cells targeting the B-cell antigen CD19 induce complete remissions in many patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) but relapses due to loss of the CD19 epitope occur in 10% to 20% of pediatric patients who initially respond. In 2015, Sotillo, Thomas-Tikhonenko, and colleagues performed copy-number analysis and whole-exome and RNA sequencing on samples from patients with B-ALL who relapsed following CD19 CAR-T cell therapy and identified hemizygous deletions spanning the CD19 locus, acquired frameshift and missense mutations in exon 2 of CD19, and alternatively spliced CD19 mRNA species lacking exon 2. The exon alterations were predicted to lead to a truncated CD19 protein lacking the extracellular domain, and expression of these mutants in B-ALL cells not only eliminated the CD19 epitope from the cell surface but also conferred a proliferative advantage and resistance to CD19 CAR-T therapy. Following this first characterization of mechanisms of clinical resistance to CAR-T cell therapy, antigen escape due to loss or downregulation of the target antigen became widely appreciated as a general mechanism of resistance to CAR-T cell therapy, spurring efforts to develop strategies to engineer CAR-T cells to achieve multispecificity or respond to lower levels of target antigen.

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