Modeling Anti-CD19 CAR T Cell Therapy in Humanized Mice with Human Immunity and Autologous Leukemia
BACKGROUND: Adoptive immunotherapy using T cells expressing chimeric antigen receptors (CARs) targeting CD19 has produced remarkable clinical outcomes. However, much of the mechanisms of action, such as the development of memory responses and sources of immune cytokines, remain elusive largely due to the challenge of characterizing human CAR T cell function in vivo. The lack of a suitable in vivo model also hinders the development of new CAR T cell therapies. METHODS: We established a humanized mouse (hu-mouse) model with a functional human immune system and genetically-matched (autologous) primary acute B-lymphoblastic leukemia (B-ALL) that permits modeling of CD19-targeted CAR T cell therapy in immunocompetent hosts without allogeneic or xenogeneic immune responses. FINDINGS: Anti-CD19 CAR T cells were detected in blood of leukemic hu-mice with kinetics and levels similar to those seen in patients receiving CAR T cell therapy. The levels of CAR T cells were correlated inversely with the burden of leukemia cells and positively with the survival times in anti-CD19 CAR T cell-treated leukemic hu-mice. Infusion of anti-CD19 CAR T cells also resulted in rapid production of T cell- and monocyte/macrophage-derived cytokines and an increase in frequency of regulatory T cells as reported in clinical studies. INTERPRETATION: These results provide a proof-of-principle that this novel preclinical model has the potential to be used to model human CAR T cell therapy and facilitate the design of new CARs with improved antitumor activity.
Jin, C., Xia, J., Rafiq, S., Huang, X., Hu, Z., Zhou, X., Brentjens, R., & Yang, Y. (2019). Modeling Anti-CD19 CAR T Cell Therapy in Humanized Mice with Human Immunity and Autologous Leukemia. EBioMedicine, 39, 173-181. https://doi.org/10.1016/j.ebiom.2018.12.013