Inspired by preclinical outcomes of low cytokine production of good anti-tumor efficacy of 4-1BB versus CD28 co-stimulation, two phase I clinical trials [102, 103] have started with optimized HER2-CARs among patients with HER2-positive malignant glioma and brain metastasis of HER2-positive breast cancer, respectively [59]. Here, ERBB2 is linked to breast cancer.