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

Abstract

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.

• Authors: Lintao Liu, Enguang Bi, Xingzhe Ma, Wei Xiong, Jianfei Qian, Lingqun Ye, Pan Su, Qiang Wang, Liuling Xiao, Maojie Yang, Yong Lu, Qing Yi
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 5902 (11 19 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 33214555 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytokines
• IFNG protein, human
• IL9 protein, human
• Interleukin-9
• Receptors, Chimeric Antigen
• Interferon-gamma

Topics

• Animals
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation
• Cytokines (metabolism)
• Cytotoxicity, Immunologic
• Humans
• Immunologic Memory
• Immunotherapy, Adoptive (methods)
• Interferon-gamma (metabolism)
• Interleukin-9 (metabolism)
• Mice
• Phenotype
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (immunology, therapy)
• Receptors, Chimeric Antigen (metabolism)
• T-Lymphocytes (cytology, immunology, metabolism, transplantation)
• Th1 Cells (cytology, immunology, metabolism, transplantation)
• Xenograft Model Antitumor Assays