Two teams have created a new generation of highly specific CAR T cells, which safely cleared solid tumors in mice with mesothelioma, ovarian cancer, and the deadly brain cancer glioblastoma while outlasting and outperforming conventional CAR T cell designs. The results suggest these cells could minimize the risk of dangerous side effects and address the traditionally poor performance of CAR T cells against solid tumors in the clinic. CAR T cells are genetically modified human T cells and have shown impressive performance in patients with leukemia. However, CAR T cells don't work as well against solid tumors, as these cancers lack molecular targets that the cells can easily recognize. Furthermore, the targets that do exist also frequently appear on healthy tissues, meaning that CAR T cells can have devastating side effects in patients with solid tumors. To address these obstacles for the treatment of glioblastoma, Joseph Choe and colleagues engineered new "prime-and-kill" molecular circuits for synNotch-CAR T cells, a cell design that only activates when it recognizes tumor antigens. The circuits integrate receptors that recognize multiple "imperfect" tumor antigens, including either the EGFRvIII receptor on glioblastoma cells or the protein MOG in healthy brain tissue. The receptors prime and activate the CAR T cells only when all the antigens are present, meaning the CAR T cells only target cancerous cells in the nervous system. The synNotch-CAR T cells shrunk glioblastoma tumors and maintained remission in mice without affecting other tissues, while more traditional CAR T cells were either ineffective or couldn't prevent tumor recurrence. Similarly, Axel Hyrenius-Wittsten and colleagues engineered synNotch-CAR T cells bearing receptors that recognize ALPPL2, a protein that appears specifically on solid tumors such as mesothelioma. This design showed strong effects and extended survival in mouse models of mesothelioma and ovarian cancer. Compared with traditional cells, the synNotch-CAR T cell designs also showed fewer signs of exhaustion, a state where CAR T cells lose their effectiveness over time. "These circuits essentially give improved capability for nuanced recognition of a tumor ... and thus open up many new possibilities for how to recognize and attack tumors in safer and more specific ways," Choe et al. say.