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

• Published in: Nature communications Vol. 11; no. 1; pp. 5902 - 14
• Main Authors: Liu, Lintao, Bi, Enguang, Ma, Xingzhe, Xiong, Wei, Qian, Jianfei, Ye, Lingqun, Su, Pan, Wang, Qiang, Xiao, Liuling, Yang, Maojie, Lu, Yong, Yi, Qing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.11.2020; Nature Portfolio
• Subjects: 13/106; 13/31; 38/109; 38/22; 38/39; 38/5; 38/88; 38/90; 38/91; 631/250/580; 631/67/1990/283/2125; 631/67/580; Animals; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cytokines - metabolism; Cytotoxicity, Immunologic; Humanities and Social Sciences; Humans; Immunologic Memory; Immunotherapy, Adoptive - methods; Interferon-gamma - metabolism; Interleukin-9 - metabolism; Mice; multidisciplinary; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors, Chimeric Antigen - metabolism; Science; Science (multidisciplinary); T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - transplantation; Th1 Cells - cytology; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - transplantation; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19672-2

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. Antigen-specific IL9-secreting CD4 Th9 and CD8 Tc9 cells have been previously characterized for their anti-tumour properties. Here, the authors show that ex vivo polarized Th9/Tc9 human CAR-T cells display increased anti-tumor activity in pre-clinical haematological and solid cancer models compared to conventional IL-2 activated CAR-T cells.