title: Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy.
abstract: B-cell malignancies upregulate the B-cell lymphoma 2 (Bcl-2) family inhibitors of the intrinsic apoptosis pathway, making them therapy resistant. However, small-molecule inhibitors of Bcl-2 family members such as ABT-737 restore a functional apoptosis pathway in cancer cells, and its oral analog ABT-263 (Navitoclax) has entered clinical trials. Gene engineered chimeric antigen receptor (CAR) T cells also show promise in B-cell malignancy, and as they induce apoptosis via the extrinsic pathway, we hypothesized that small-molecule inhibitors of the Bcl-2 family may potentiate the efficacy of CAR T cells by engaging both apoptosis pathways. CAR T cells targeting CD19 were generated from healthy donors as well as from pre-B-ALL (precursor-B acute lymphoblastic leukemia) patients and tested together with ABT-737 to evaluate apoptosis induction in five B-cell tumor cell lines. The CAR T cells were effective even if the cell lines exhibited different apoptosis resistance profiles, as shown by analyzing the expression of apoptosis inhibitors by PCR and western blot. When combining T-cell and ABT-737 therapy simultaneously, or with ABT-737 as a presensitizer, tumor cell apoptosis was significantly increased. In conclusion, the apoptosis inducer ABT-737 enhanced the efficacy of CAR T cells and could be an interesting drug candidate to potentiate T-cell therapy.
authors.forename: H
authors.initials: H
authors.lastname: Karlsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. hannah.karlsson@igp.uu.se
authors.forename: S C H
authors.initials: SC
authors.lastname: Karlsson
authors.forename: A C
authors.initials: AC
authors.lastname: Lindqvist
authors.forename: M
authors.initials: M
authors.lastname: Fransson
authors.forename: G
authors.initials: G
authors.lastname: Paul-Wetterberg
authors.forename: B
authors.initials: B
authors.lastname: Nilsson
authors.forename: M
authors.initials: M
authors.lastname: Essand
authors.forename: K
authors.initials: K
authors.lastname: Nilsson
authors.forename: P
authors.initials: P
authors.lastname: Frisk
authors.forename: H
authors.initials: H
authors.lastname: Jernberg-Wiklund
authors.forename: A
authors.initials: A
authors.lastname: Loskog
authors.forename: S I A
authors.initials: SI
authors.lastname: Loskog
mesh_terms: D018941:Antigens, CD19 / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051940:B7-2 Antigen / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
chemical_list: C501332:ABT-737; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D051940:B7-2 Antigen; D001713:Biphenyl Compounds; C491901:FAS protein, human; D006680:HLA Antigens; C573420:ICAM1 protein, human; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1