Development and clinical evaluation of non-viral genome specific targeted CAR T cells in relapsed/refractory B-cell non-Hodgkin lymphoma
Zhang, J.; Hu, Y.; Yang, J.; Li, W.; Tian, Y.; Wei, G.; Zhang, L.; Zhao, K.; Qi, Y.; Tan, B.; Zhang, M.; Li, Y.; Tian, Q.; Fang, C.; Wu, Y.; Li, D.; Du, B.; Liu, M.; Huang, H.
Show abstract
In recent years, chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating hematological malignancies. However, using virus in manufacture of CAR T cells brings about several problems. The application of CRISPR/Cas9 genome editing technology emerges in constructing novel CAR T cells by disrupting endogenous genes. Here we successfully develop a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. By targeting a CAR in AAVS1 safe harbor locus, we demonstrated that these CAR T cells behave comparable to those conventionally produced by lentivirus. Furthermore, PD1-knockin anti-CD19 CAR T cells show a superior ability to eradicate tumor cells with high PD-L1 expression. In the adoptive therapy for relapsed/refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL), we observed durable responses without serious adverse events and complete remission (CR) in patients treated with these PD1 knockout CAR T cells. Collectively, our results prove the safety and feasibility of non-viral genome specific integrated CAR T cells, thus providing a new potential strategy for cancer treatment using these novel CAR T cells.
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