B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric and adolescent cancer in the United States. Treatment of B-ALL has improved greatly in recent years, thanks to CAR-T cell therapy and other therapies that alter the body’s T cells so they can target CD19—a protein that is overexpressed on nearly all B-cell cancer cells. However, treatment-resistant relapses can occur when patients develop cell populations with low expression of CD19; such cases account for 30-40% of all relapses affecting CAR-T-treated patients.

In a paper published online on February 20 in the Journal of Clinical Investigation, Amit Verma, M.B.B.S., and colleagues found that CD19-resistant cells evade CD19-targeted therapies by decreasing expression of both CD19 and CD22—meaning that C22 would be a poor target for patients with CD19-resistant B-ALL. The researchers then compared differences in gene expression of treatment-sensitive and CD19-resistant cancer cells; they found that BTK signaling, a part of the BCR signaling pathway, was maintained in CD19-resistant cells—which also proved more sensitive to BTK and BCR-inhibitor drugs approved for use against other types of cancer but have not yet been rigorously evaluated against treatment-resistant B-ALL. The finding suggests that use of BTK and BCR inhibitors could be an effective treatment strategy for patients who have CD19-resistant B-ALL.

Dr. Verma is associate director of translational science at the National Cancer Institute–designated Montefiore Einstein Comprehensive Cancer Center, director of the division of hemato-oncology in the department of oncology at Albert Einstein College of Medicine and Montefiore Health System, and professor of oncology, of medicine and of developmental and molecular biology at Einstein. The paper’s first authors are: Sarah Aminov, a Ph.D. student in Dr. Verma’s lab, Orsi Giricz, Ph.D., previously a senior scientist in Verma’s lab, now a senior director of research programs & communication at the Leukemia and Lymphoma Society, and R. Alejandro Sica, M.D., assistant professor of oncology at Einstein, and David T. Melnekoff at Mount Sinai. Other senior authors are Nirali N. Shah, M.D., at the National Cancer Institute, Joshua D. Brody, M.D., and Samir Parekh, M.D., all at Mount Sinai.