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Int J Cancer. 2016 Oct 15;139(8):1799-809. doi: 10.1002/ijc.30217. Epub 2016 Jun 11.

Chimeric antigen receptor-engineered cytokine-induced killer cells overcome treatment resistance of pre-B-cell acute lymphoblastic leukemia and enhance survival.

Author information

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.
9
German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Germany.

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.

KEYWORDS:

B-ALL; CD19; adoptive immunotherapy; chimeric antigen receptor; cytokine-induced killer cells

PMID:
27253354
DOI:
10.1002/ijc.30217
[Indexed for MEDLINE]
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