In vivo CRISPR screen identifies gene edits that strengthen CAR-T therapy against solid tumors
For patients with blood cancers like leukemia and lymphoma, the immunotherapy known as CAR-T cell therapy can be lifesaving. Doctors remove a patient's immune cells, called T cells, engineer them in the lab to better recognize and attack cancer, and infuse them back into the bloodstream. But for solid tumors—which include lung, pancreatic, ovarian, colon, breast and other cancer types—these…
Scientists at Gladstone Institutes and UCSF have identified genetic edits that enhance CAR-T cells' ability to combat solid tumors. The breakthrough, published in Nature, utilized the world's first in vivo genome-wide CRISPR screen in human T cells within living mice. This platform enabled researchers to study gene edits on CAR-T cells in a real organism, overcoming previous limitations of lab dish experiments.
Two specific gene edits were found to significantly improve CAR-T cell performance in solid tumors. T cells lacking the P2RY8 gene infiltrated tumors more effectively, while T cells with altered GNAS produced higher levels of interferon-gamma, a key signal for cancer-fighting activity. CAR-T cells with these genetic modifications exhibited improved efficacy in multiple mouse models of solid cancers, including melanoma, lung cancer, pancreatic cancer, and uterine sarcoma. The discovery offers new hope for developing more effective cell therapies against solid tumors.
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