Targeting Triple-Negative Breast Cancer with Combination Therapy of EGFR CAR T Cells and CDK7 Inhibition

EGFR-targeted chimeric antigen receptor (CAR) T cells are potent and specific in suppressing the growth of triple-negative breast cancer (TNBC) in vitro and in vivo. However, in this study, a subset of mice soon acquired resistance, which limits the potential use of EGFR CAR T cells. We aimed to find a way to overcome the observed resistance. Transcriptomic analysis results revealed that EGFR CAR T-cell treatment induced a set of immunosuppressive genes, presumably through IFNγ signaling, in EGFR CAR T-cell–resistant TNBC tumors. The EGFR CAR T-cell–induced immunosuppressive genes were associated with EGFR CAR T-cell–activated enhancers and were especially sensitive to THZ1, a CDK7 inhibitor we screened out of a panel of small molecules targeting epigenetic modulators. Accordingly, combination therapy with THZ1 and EGFR CAR T cells suppressed immune resistance, tumor growth, and metastasis in TNBC tumor models, including human MDA-MB-231 cell–derived and TNBC patient–derived xenografts, and mouse EMT6 cell–derived allografts. Taken together, we demonstrated that transcriptional modulation using epigenetic inhibitors could overcome CAR T-cell therapy–induced immune resistance, thus providing a therapeutic avenue for treating TNBC in the clinic.