CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells

Mario Bunse, Janina Pfeilschifter, Julia Bluhm, Maria Zschummel, Jara J. Joedicke, Anthea Wirges, Helen Stark, Vivien Kretschmer, Markus Chmielewski, Wolfgang Uckert, Hinrich Abken, Jörg Westermann, Armin Rehm () and Uta E. Höpken ()
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Mario Bunse: Department of Microenvironmental Regulation in Autoimmunity and Cancer
Janina Pfeilschifter: Department of Microenvironmental Regulation in Autoimmunity and Cancer
Julia Bluhm: Department of Translational Tumorimmunology
Maria Zschummel: Department of Microenvironmental Regulation in Autoimmunity and Cancer
Jara J. Joedicke: Department of Microenvironmental Regulation in Autoimmunity and Cancer
Anthea Wirges: Department of Translational Tumorimmunology
Helen Stark: Department of Translational Tumorimmunology
Vivien Kretschmer: Department of Microenvironmental Regulation in Autoimmunity and Cancer
Markus Chmielewski: University Hospital Cologne
Wolfgang Uckert: Department of Molecular Cell Biology and Gene Therapy
Hinrich Abken: University Hospital Regensburg
Jörg Westermann: Department of Hematology, Oncology and Tumorimmunology
Armin Rehm: Department of Translational Tumorimmunology
Uta E. Höpken: Department of Microenvironmental Regulation in Autoimmunity and Cancer

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract CAR-T cell therapy targeting CD19 demonstrated strong activity against advanced B cell leukemia, however shows less efficacy against lymphoma with nodal dissemination. To target both B cell Non-Hodgkin’s lymphoma (B-NHLs) and follicular T helper (Tfh) cells in the tumor microenvironment (TME), we apply here a chimeric antigen receptor (CAR) that recognizes human CXCR5 with high avidity. CXCR5, physiologically expressed on mature B and Tfh cells, is also highly expressed on nodal B-NHLs. Anti-CXCR5 CAR-T cells eradicate B-NHL cells and lymphoma-supportive Tfh cells more potently than CD19 CAR-T cells in vitro, and they efficiently inhibit lymphoma growth in a murine xenograft model. Administration of anti-murine CXCR5 CAR-T cells in syngeneic mice specifically depletes endogenous and malignant B and Tfh cells without unexpected on-target/off-tumor effects. Collectively, anti-CXCR5 CAR-T cells provide a promising treatment strategy for nodal B-NHLs through the simultaneous elimination of lymphoma B cells and Tfh cells of the tumor-supporting TME.

Date: 2021
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DOI: 10.1038/s41467-020-20488-3

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