After observing that CD80 and/or CD86 expression are upregulated in most patients with DLBCL receiving CAR T cell therapy, Prinz et al. designed an “AND” switch CAR T construct consisting of a 1st generation CD19-targeted CAR co-expressed with an extracellular CTLA-4 domain (Chimeric Checkpoint Receptor) fused to a 4-1BB costimulatory domain (CAR/CCR). Compared to 2nd generation CD19+ CAR T cells, CAR/CCR T cells showed superior and longer-lasting efficacy in xenograft models, while sparing healthy B cells and CD19+ metaneural pericytes in vitro. Improved antitumor activity was also associated with decreased levels of IL-2 and IL-6.
Contributed by Katherine Turner
ABSTRACT: Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only _40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated with tisagenlecleucel. This finding leads to the development of the CAR/CCR (chimeric checkpoint receptor) design, which consists of a CD19-specific first-generation CAR co-expressed with a recombinant CTLA-4-linked receptor with a 4-1BB co-stimulatory domain. CAR/CCR T cells demonstrate superior efficacy in xenograft mouse models compared with CAR T cells, superior long-term activity, and superior selectivity in in vitro assays with non-malignant CD19(+) cells. In addition, immunocompetent mice show an intact CD80(-)CD19(+) B cell population after CAR/CCR T cell treatment. The results reveal the CAR/CCR design as a promising strategy for further translational study.
Author Info: (1) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. Electronic address
Author Info: (1) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. Electronic address: lars.prinz1@uk-koeln.de. (2) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (3) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (4) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (5) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (6) Heidelberg University, 69117 Heidelberg, Germany. (7) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (8) Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (9) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (10) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany. (11) Institute of Pathology, University Hospital Cologne, 50937 Cologne, Germany. (12) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (13) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (14) Department of Hematology, Oncology and Tumorimmunology, Charit University Medical Center Berlin, Benjamin Franklin Campus, 12203 Berlin, Germany. (15) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany. (16) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA. (17) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Dsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany; University Hospital Essen, Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, Hufelandstr. 55, 45147 Essen, Germany. (18) University Hospital Essen, Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, Hufelandstr. 55, 45147 Essen, Germany. (19) University Hospital Essen, Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, Hufelandstr. 55, 45147 Essen, Germany. (20) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany. (21) Institute of Pathology, University Hospital Cologne, 50937 Cologne, Germany. (22) Department of Hematology, Oncology and Tumorimmunology, Charit University Medical Center Berlin, Benjamin Franklin Campus, 12203 Berlin, Germany. (23) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. (24) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany. (25) Department I of Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany. Electronic address: markus.chmielewski@uk-koeln.de.
