Death receptor pathway drives resistance to CAR T cell therapy

Death receptor pathway drives resistance to CAR T cell therapy

Some cancer cells refuse to die, even in the face of powerful cellular immunotherapies like CAR T cell therapy, and new research from the Abramson Cancer Center of the University of Pennsylvania is shedding light on why. In a new study, researchers describe how a death receptor pathway in the cancer cell itself plays a central role in determining its response to CAR T cells. It's the first study to show that natural cancer features can influence response to CAR T cells, and that cancer cells can drive the development of CAR T cell dysfunction. The findings may provide guidance for future immunotherapies in patients whose blood cancers are resistant to CAR T therapy. The findings published today in Cancer Discovery , a journal of the American Association for Cancer Research. CAR T cell therapy modifies patients' own immune T cells, which are collected and reprogrammed to potentially seek and destroy cancer cells. After being infused back into patients' bodies, these cells both multiply and attack, targeting cells that express a protein called CD19. In acute lymphoblastic leukemia (ALL), between 10 and 20 percent of patients have disease that is resistant to CAR T cells, but until now, researchers did not understand why. Most theories have centered around a defect in the T cells, but what we've shown here is that the problem originates in an important death signaling pathway in the cancer cell itself, which prevents the T cell from doing its job," Marco Ruella, MD, study's co-senior author and assistant professor of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania Ruella is also a member of the Center for Cellular Immunotherapies in Penn's Abramson Cancer Center. Ruella's co-senior author is Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology at Penn. Researchers first performed a genome-wide CRISPR/Cas9-based screen of an ALL cell line known as Nalm6 to isolate pathways associated with resistance. CRISPR is a gene-editing tool that can effectively target specific stretches of genetic code, as well as modify DNA at precise locations for experiments and in some instances treatment. Cells were edited for loss of function of single genes and combined with CAR T cells for 24 hours to identify the pathway driving the primary resistance. Related Stories



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