To overcome the general downsides of CAR T cell therapy, such as B cell toxicity and potential antigen loss, Märkl and Schultheiß et al. constructed CAR T cells with selective specificity for the B cell receptor light chain neoepitope driver mutation, IGLV3-21R110 (associated with an aggressive clinical course in CLL). Humanized anti-IGLV3-21R110 healthy donor- or CLL patient-derived CAR T cells specifically lysed IGLV3-21R110-positive cell lines or primary CLL cells, while sparing wild-type cells in vitro and healthy polyclonal B cells in humanized mouse models. CLL patient-derived CAR T cells mediated lysis of autologous IGLV3-21R110-positive CLL cells in a xenograft model.
Contributed by Ute Burkhardt
ABSTRACT: The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we use a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21(R110)) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We develop murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicate IGLV3-21(R110) expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21(G110) light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21(R110) expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.
Author Info: (1) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (2) Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. Laborator
Author Info: (1) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (2) Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. (3) Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. (4) Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA. (5) Faculty of Biology, University of Freiburg, Freiburg, Germany. (6) Cellular Immunotherapy, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (7) Cellular Immunotherapy, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (8) Cellular Immunotherapy, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland. (9) Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. (10) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (11) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (12) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (13) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (14) Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. Laboratory of Cancer Immunotherapy, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. (15) Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. Laboratory of Cancer Immunotherapy, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. (16) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (17) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. (18) AVA-lifescience GmbH, Ferdinand-Porsche-Stra§e 5/1, Denzlingen, Germany. (19) Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. (20) Medizinische Klinik und Poliklinik II, Universittsklinikum Wrzburg, Wrzburg, Germany. (21) Medizinische Klinik und Poliklinik II, Universittsklinikum Wrzburg, Wrzburg, Germany. (22) Faculty of Biology, University of Freiburg, Freiburg, Germany. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany. (23) Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA. (24) Division of Clinical Pharmacology, Klinikum der Universitt Mnchen, Munich, Germany. sebastian.kobold@med.uni-muenchen.de. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. sebastian.kobold@med.uni-muenchen.de. Einheit fr Klinische Pharmakologie (EKLiP), Helmholtz Munich, Research Center for Environmental Health (HMGU), Neuherberg, Germany. sebastian.kobold@med.uni-muenchen.de. (25) Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. Mascha.Binder@unibas.ch. Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland. Mascha.Binder@unibas.ch.
