Chimeric antigen receptor‐engineered cytokine‐induced killer cells overcome treatment resistance of pre‐B‐cell acute lymphoblastic leukemia and enhance survival |
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| Authors: | Sarah Oelsner Juliane Wagner Miriam E. Friede Verena Pfirrmann Sabrina Genßler Eva Rettinger Christian J. Buchholz Heike Pfeifer Ralf Schubert Oliver G. Ottmann Evelyn Ullrich Winfried S. Wels |
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| Affiliation: | 1. Georg‐Speyer‐Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany;2. Division for Stem Cell Transplantation and Immunology, Hospital for Children and Adolescents, Goethe University, Frankfurt, Germany;3. LOEWE Center for Cell and Gene Therapy, Goethe University, Frankfurt, Germany;4. Molecular Biotechnology and Gene Therapy, Paul‐Ehrlich‐Institut, Langen, Germany;5. German Cancer Consortium (DKTK), Heidelberg, Germany;6. Department of Medicine, Hematology and Oncology, Goethe University, Frankfurt, Germany;7. Division for Allergology, Pneumology and Cystic Fibrosis, Hospital for Children and Adolescents, Goethe University, Frankfurt, Germany;8. Department of Haematology, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom |
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| Abstract: | Pre‐emptive cancer immunotherapy by donor lymphocyte infusion (DLI) using cytokine‐induced killer (CIK) cells may be beneficial to prevent relapse with a reduced risk of causing graft‐versus‐host‐disease. CIK cells are a heterogeneous effector cell population including T cells (CD3+ CD56?), natural killer (NK) cells (CD3?CD56+) and natural killer T (T‐NK) cells (CD3+ CD56+) that exhibit non‐major histocompatibility complex (MHC)‐restricted cytotoxicity and are generated by ex vivo expansion of peripheral blood mononuclear cells in the presence of interferon (IFN)‐γ, anti‐CD3 antibody, interleukin‐2 (IL‐2) and interleukin‐15 (IL‐15). To facilitate selective target‐cell recognition and enhance specific cytotoxicity against B‐cell acute lymphoblastic leukemia (B‐ALL), we transduced CIK cells with a lentiviral vector encoding a chimeric antigen receptor (CAR) that carries a composite CD28‐CD3ζ domain for signaling and a CD19‐specific scFv antibody fragment for cell binding (CAR 63.28.z). In vitro analysis revealed high and specific cell killing activity of CD19‐targeted CIK/63.28.z cells against otherwise CIK‐resistant cancer cell lines and primary B‐ALL blasts, which was dependent on CD19 expression and CAR signaling. In a xenograft model in immunodeficient mice, treatment with CIK/63.28.z cells in contrast to therapy with unmodified CIK cells resulted in complete and durable molecular remissions of established primary pre‐B‐ALL. Our results demonstrate potent antileukemic activity of CAR‐engineered CIK cells in vitro and in vivo, and suggest this strategy as a promising approach for adoptive immunotherapy of refractory pre‐B‐ALL. |
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| Keywords: | adoptive immunotherapy B‐ALL cytokine‐induced killer cells chimeric antigen receptor CD19 |
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