Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy

Cancer Gene Ther. 2013 Jul;20(7):386-93. doi: 10.1038/cgt.2013.35. Epub 2013 Jun 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD19 / immunology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • B7-2 Antigen / metabolism
  • Biphenyl Compounds / pharmacology*
  • Cell Line, Tumor
  • Coculture Techniques
  • Combined Modality Therapy
  • Cytotoxicity, Immunologic
  • Gene Expression
  • HLA Antigens / metabolism
  • Humans
  • Immunotherapy
  • Intercellular Adhesion Molecule-1 / metabolism
  • Nitrophenols / pharmacology*
  • Phenotype
  • Piperazines / pharmacology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Receptors, Antigen, T-Cell / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Sulfonamides / pharmacology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • fas Receptor / metabolism


  • ABT-737
  • Antigens, CD19
  • Antineoplastic Agents
  • B7-2 Antigen
  • Biphenyl Compounds
  • FAS protein, human
  • HLA Antigens
  • ICAM1 protein, human
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Sulfonamides
  • fas Receptor
  • Intercellular Adhesion Molecule-1