Enhancing CAR-T Cell Therapy by Preventing Cellular Stalling to Boost Tumor Fight

Chimeric antigen receptor (CAR)-T cells, engineered from a patient's own T cells, are at the forefront of cancer immunotherapy. They are designed to specifically target and destroy cancer cells, but a significant challenge has been their limited ability to survive long enough within the body to comprehensively eradicate tumors. After infusion, CAR-T cells often rapidly expand upon encountering tumor cells; however, they tend to decline due to a natural process known as activation-induced cell death, which hampers their sustained anti-tumor activity.

Recent research published in Science Translational Medicine has uncovered a promising approach to address this limitation. The study focused on modifying CAR-T cells to partially avoid activation-induced cell death, thereby increasing their longevity and effectiveness. A key cytokine involved in CAR-T cell activity is interferon-gamma (IFNg), which, when released in large quantities, can cause toxicities in patients. To mitigate this, scientists engineered CAR-T cells that do not produce IFNg.

Interestingly, while these IFNg-deficient CAR-T cells exhibited reduced inflammation in blood cancers, they were less effective against solid tumors. The breakthrough came when researchers knocked out the receptor for IFNg (IFNgR) on the CAR-T cells using CRISPR/Cas9 technology. By preventing these cells from responding to IFNg signals, they reduced cell death after activation, enhanced their expansion, and prolonged their survival.

The modified CAR-T cells were tested both in vitro and in mouse models bearing tumors. Results demonstrated that knocking out IFNgR led to improved persistence, greater expansion, and increased anti-tumor activity. These insights suggest that disabling IFNg signaling pathways can prevent CAR-T cell stalling and improve their therapeutic durability across various tumor types. The team plans to initiate clinical trials to evaluate the safety and efficacy of these enhanced CAR-T cells in patients with solid tumors.

This innovative strategy holds promise for broadening the application of CAR-T cell therapy, making it more effective for patients with challenging solid tumors by prolonging cell survival and boosting their ability to eradicate cancer cells.