Gene edits make CAR-T cells effective against solid tumors

Scientists at Gladstone Institutes and UC San Francisco have identified two genetic edits that make CAR-T cells far more effective against solid tumors, a longstanding barrier in cancer immunotherapy. The findings, published in Nature on August 12, represent the first genome-wide CRISPR screen conducted in human T cells inside living animals.medicalxpress+1

A Platform That Changes the Game

CAR-T cell therapy has proven lifesaving for blood cancers like leukemia and lymphoma, but solid tumors — including lung, pancreatic, and ovarian cancers — have largely resisted the approach. The hostile tumor microenvironment suppresses and excludes engineered immune cells before they can do their work.medicalxpress

The breakthrough came from a new screening method developed by postdoctoral researcher Qi Liu and senior author Julia Carnevale. By engineering tumor cells to display a signal that attracts T cells, the team was able to recover millions of human T cells from each tumor in mice — far more than previous methods allowed — making genome-scale screens statistically feasible for the first time.gladstone+1

Two Genes, One Powerful Combination

Among nearly 20,000 genes tested, two stood out. Removing P2RY8 allowed T cells to flood into tumors in greater numbers by disabling a molecular brake that normally restricts immune cell trafficking. Removing GNAS — which acts as a central hub for processing suppressive signals from the tumor environment — enabled T cells to maintain their cancer-fighting activity and produce higher levels of interferon-gamma.biorxiv+1

"What we found is that many of those off switches run through one shared circuit, and disabling GNAS let the T cells stop listening to all of them at once," Liu said.medicalxpress

CAR-T cells lacking GNAS shrank tumors across multiple mouse models including melanoma, lung cancer, pancreatic cancer, gastroesophageal adenocarcinoma, and uterine sarcoma. Combining both edits produced even greater results: at a very low CAR-T cell dose, two-thirds of mice in a lung cancer model were tumor-free at the study's end, compared with none that received control-edited T cells.biorxiv+1

Path to the Clinic

The edits also worked in patient-derived T cells from people with ovarian cancer and melanoma. Mice tracked for more than six months after tumor clearance showed no long-term side effects, and the edited cells appeared normal outside the tumor environment.medicalxpress

"We now have a way to run these screens across the entire genome inside a living animal, and that changes what we can discover," said Alex Marson, director of the Gladstone–UCSF Institute of Genomic Immunology. "We think it fundamentally expands what's possible for developing the next generation of cell therapies."gladstone+1