Low-affinity HER2 CAR T cells and antitumor efficacy
Shabaneh TB, Stevens AR, Stull SM, et al. Systemically Administered Low-Affinity HER2 CAR T Cells Mediate Antitumor Efficacy Without Toxicity. Journal for ImmunoTherapy of Cancer. 2024; 12 (2) (doi: 10.1136/jitc-2023-008566).
Preclinical evidence identifies human epidermal growth factor receptor 2 (HER2) as a promising candidate for chimeric antigen receptor (CAR) T-cell therapy in solid cancers but it is best to design the cells with low affinity for the target. Because HER is expressed on healthy and cancerous tissues, on-target off-tumor toxicity is a concern. Mouse models showed that CAR T cells engineered to have high affinity for HER2 gravitated toward normal HER2-positive tissues instead of tumors. In the normal cells, they triggered toxic results with no improvement in anti-tumor efficacy. When they did infiltrate tumors, the level of anti-tumor activity was unimpressive. But low-affinity HER CAR-T spared normal HER2-positive tissues while successfully infiltrating HER2-positive tumors. Under these circumstances, tumor control was achieved without introducing toxicity. Researchers also report that low-affinity HER2 CAR-T can be safely and systemically administered with lymphodepletion — intensity levels for which, along with titration of T-cell dose, should be the next focus as the science advances.