Targeting triple negative breast cancer with combination therapy of epidermal growth factor receptor-targeted chimeric antigen receptor T cell and CDK7 inhibitor

Epidermal growth factor receptor-targeted chimeric antigen receptor T cell (EGFR CAR-T) is potent and specific in suppressing triple-negative breast cancer (TNBC) cell growth in vitro and in vivo. However, a subset of mice soon acquired resistance, which limits the potential use of EGFR CAR-T. The aim of this study is to find a way to overcome the observed resistance. Transcriptomic analysis results revealed that EGFR CAR-T treatment led to the induction of a cohort of immunosuppressive genes, presumably through Interferon gamma (IFNγ signaling, in EGFR CAR-T-resistant TNBC tumors. EGFR CAR-T-induced immunosuppressive genes were found to be associated with EGFR CAR-T-activated enhancers and especially sensitive to THZ1, a CDK7 inhibitor, out of a panel of small molecules targeting epigenetic modulators screened. Accordingly, combination therapy of THZ1 and EGFR CAR-T suppressed immune resistance and tumor growth and metastasis in TNBC tumor models including human MDA-MB-231 cells-derived xenografts, TNBC patient-derived xenografts, and mouse EMT6 cells-derived allografts in mice. Taken together, we demonstrated that CAR-T therapy-induced immune resistance can be overcome by transcriptional modulation using epigenetic inhibitors, providing a therapeutic avenue for treating TNBC in the clinic. RNA-seq was performed to identify differential genes in MBA-MB-231 in different condition.