A new study published in Clinical Cancer Research highlights several strategies that could improve CAR T-cell therapy for pancreatic ductal adenocarcinoma (PDAC), a cancer that has remained largely resistant to immunotherapy. Researchers tested a mesothelin-targeting CAR T-cell treatment in combination with different approaches designed to overcome the tumor’s protective barriers.
One strategy used aderbasib to prevent the shedding of mesothelin, a protein targeted by CAR T cells. While the drug increased mesothelin levels on cancer cells in laboratory experiments, it did not significantly improve tumor control in animal models.
A second approach combined CAR T cells with ibrutinib, a drug commonly used for blood cancers. This combination helped prevent T-cell exhaustion, increased the number of active immune cells, and improved their ability to attack tumors.
Researchers also found that blocking the PD-1 immune checkpoint restored CAR T-cell activity against tumors with high levels of PD-L1, a protein that suppresses immune responses.
The study further showed that delivering CAR T cells directly into the abdominal cavity produced better tumor control and stronger T-cell activity than intravenous administration. Future research will focus on engineering next-generation CAR T cells that can better penetrate tumors and resist the immunosuppressive tumor environment.