title: Chimeric antigen receptor T cells targeting Fc μ receptor selectively eliminate CLL cells while sparing healthy B cells.
abstract: Adoptive cell therapy of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR)-modified T cells targeting CD19 induced lasting remission of this refractory disease in a number of patients. However, the treatment is associated with prolonged "on-target off-tumor" toxicities due to the targeted elimination of healthy B cells demanding more selectivity in targeting CLL cells. We identified the immunoglobulin M Fc receptor (FcμR), also known as the Fas apoptotic inhibitory molecule-3 or TOSO, as a target for a more selective treatment of CLL by CAR T cells. FcμR is highly and consistently expressed by CLL cells; only minor levels are detected on healthy B cells or other hematopoietic cells. T cells with a CAR specific for FcμR efficiently responded toward CLL cells, released a panel of proinflammatory cytokines and lytic factors, like soluble FasL and granzyme B, and eliminated the leukemic cells. In contrast to CD19 CAR T cells, anti-FcμR CAR T cells did not attack healthy B cells. T cells with anti-FcμR CAR delayed outgrowth of Mec-1-induced leukemia in a xenograft mouse model. T cells from CLL patients in various stages of the disease, modified by the anti-FcμR CAR, purged their autologous CLL cells in vitro without reducing the number of healthy B cells, which is the case with anti-CD19 CAR T cells. Compared with the currently used therapies, the data strongly imply a superior therapeutic index of anti-FcμR CAR T cells for the treatment of CLL.
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany;
authors.forename: Elena
authors.initials: E
authors.lastname: Faitschuk
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany;
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Hombach
authors.affiliation: Department I Internal Medicine, University Hospital Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; and.
authors.forename: Lukas P
authors.initials: LP
authors.lastname: Frenzel
authors.affiliation: Department I Internal Medicine, University Hospital Cologne, Cologne, Germany; Klinikum Schwabing, Munich, Germany.
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany;
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D060846:Cell Engineering; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015202:Protein Engineering; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011961:Receptors, Fc / Q000037:antagonists & inhibitors* / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011948:Receptors, Antigen, T-Cell; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C035311:immunoglobulin M receptor