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 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 are published 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,” says the study’s co-senior author Marco Ruella, an assistant professor of hematology-oncology in the Perelman School of Medicine and a member of the Center for Cellular Immunotherapies in Penn’s Abramson Cancer Center. Ruella’s co-senior author is Saar Gill, an assistant professor of hematology-oncology at Penn.
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