CAR-T therapies targeting the CD19 molecule have been approved for treating blood cancers. Though many patients respond well, about half eventually relapse because cancer cells remove the CD19 target from their surfaces. A team led by Ludwig Stanford’s Crystal Mackall and her Stanford colleague David Miklos examined the roots of CAR-T escape in lymphoma patients and tested a strategy to overcome that resistance. They reported in a July paper in Nature Medicine that lymphoma cells too escape CAR-T targeting by reducing CD19 expression. Most notably, their analysis of lymphoma patients revealed that those whose cancers express fewer than 3,000 CD19 molecules per cancer cell are most likely to relapse—establishing a valuable method to select patients for CAR-T therapy. The researchers also devised CAR T-cells that simultaneously target CD19 and another antigen, CD22, and tested them in 38 patients with B cell acute lymphocytic leukemia and large B cell lymphoma. All leukemia patients initially responded, while just 13 of 21 lymphoma patients did. But a good number in both groups ultimately relapsed because the CAR-T cells were preferentially targeting the CD19 molecule, which lymphoma cells removed from their surfaces. The researchers aim to develop bispecific CAR T-cells that target CD22 and CD19 with equal vigor.
This article appeared in the February 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).