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Ludwig researchers engineer CAR-T cells to resist exhaustion, attack solid tumors in mice

DECEMBER 10, 2019, New York— A team led by researcher Crystal Mackall of the Ludwig Center at Stanford has developed a new approach to programming cancer-fighting immune cells known as CAR-T cells that prolongs their activity and increases their effectiveness against human cancer cells grown in the laboratory and in mice. Their paper was published in the December 4 issue of Nature.

“We know that T cells are powerful enough to eradicate cancer,” said Crystal Mackall, the Ernest and Amelia Gallo Family Professor and professor of pediatrics and of medicine at the Stanford University School of Medicine. “But these same T cells have evolved to have natural brakes that tamp down the potency of their response after a period of prolonged activity. We’ve developed a way to mitigate this exhaustion response and improve the activity of CAR-T cells against blood and solid cancers.”

Although blood cancers often respond impressively to CAR-T treatment, fewer than half of treated patients experience long-term control of their disease, often because the CAR-T cells become exhausted, losing their ability to proliferate robustly and attack cancer cells.

Mackall turned to a technique co-developed in the laboratory of Howard Chang, the Virginia and D.K. Ludwig Professor of Cancer Genomics and professor of genetics at Stanford, to figure out what happens when T cells become exhausted. The technique, ATAC-Seq, pinpoints areas of the genome where regulatory circuits control the levels at which specific genes are expressed. The researchers discovered that exhausted T cells have an imbalance in the activity of a class of genes that regulate protein levels in the cells, which causes an increase in proteins that inhibit their activity.

When the researchers modified CAR-T cells to restore the balance by overexpressing c-Jun, a gene that increases the expression of proteins associated with T cell activation, the cells remained active and proliferated in the laboratory even under conditions that would normally result in their exhaustion. Mice injected with human leukemia cells lived longer when treated with the modified CAR-T cells than with the regular ones. In addition, the c-Jun expressing CAR-T cells reduced the tumor burden and extended the lifespan of laboratory mice with the human bone cancer osteosarcoma.

“Although more work needs to be done to test this in humans, we’re hopeful that our findings will lead to the next generation of CAR-T cells and make a significant difference for people with many types of cancers,” said Mackall, who hopes to begin clinical trials of the new CAR-T cells within 18 months, beginning with patients diagnosed with leukemia.

The Stanford Medicine press release from which this summary is derived is available here.


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