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Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9.

Lintao LiuEnguang BiXingzhe MaWei XiongJianfei QianLingqun YePan SuQiang WangLiuling XiaoMaojie YangYong LuQing Yi
Published in: Nature communications (2020)
CAR-T cell therapy is effective for hematologic malignancies. However, considerable numbers of patients relapse after the treatment, partially due to poor expansion and limited persistence of CAR-T cells in vivo. Here, we demonstrate that human CAR-T cells polarized and expanded under a Th9-culture condition (T9 CAR-T) have an enhanced antitumor activity against established tumors. Compared to IL2-polarized (T1) cells, T9 CAR-T cells secrete IL9 but little IFN-γ, express central memory phenotype and lower levels of exhaustion markers, and display robust proliferative capacity. Consequently, T9 CAR-T cells mediate a greater antitumor activity than T1 CAR-T cells against established hematologic and solid tumors in vivo. After transfer, T9 CAR-T cells migrate effectively to tumors, differentiate to IFN-γ and granzyme-B secreting effector memory T cells but remain as long-lived and hyperproliferative T cells. Our findings are important for the improvement of CAR-T cell-based immunotherapy for human cancers.
Keyphrases
  • endothelial cells
  • cell therapy
  • induced pluripotent stem cells
  • dendritic cells
  • end stage renal disease
  • immune response
  • newly diagnosed
  • chronic kidney disease
  • regulatory t cells
  • young adults
  • bone marrow