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Immunotherapy of B-cell malignancies with genetically engineered human CD8+ natural killer T cells

Leukemia volume 20, pages 729–732 (2006)Cite this article

Adoptive T-cell immunotherapy is an attractive modality for the treatment of human hematologic malignancies. Genetic engineering of T lymphocytes with chimeric T-cell receptors (cTCR) has been shown to be a potent strategy for targeted immunotherapy.1 A variety of cTCR have been constructed, some of which consist of a single-chain antibody variable fragment (scFv) with tumor antigen specificity linked to the constant region of the CD3ζ-chain of the TCR.2 cTCR expressing T lymphocytes can bypass MHC-restricted target recognition and have shown significant tumor responses in models. However, clinical efficacy in humans is, as yet limited. The reasons for this are not well understood, but incomplete activation via the signaling domain of the CD3ζ-chain is thought to be one major limitation for successful clinical application.3

In this study, cellular cytotoxicity of ex vivo expanded human CD8+ natural killer T (NKT) cells was redirected using CD20 antigen-specific cTCR as a novel approach to cellular immunotherapy for B-cell malignancies. CD8+ NKT cells are found in small percentages in human peripheral blood or bone marrow and readily expanded in culture by timed addition of interferon-γ (IFN-γ), followed by α-CD3 antibody and interleukin-2 (IL-2).4 Ex vivo expanded CD8+ NKT cells coexpress surface markers of both T cells (CD3, CD8, αβTCR) and natural killer (NK) cells (CD56). These immunological effector cells, which also have been referred to as cytokine-induced killer (CIK) cells, show potent MHC-unrestricted cytotoxicity against various tumor cell lines and fresh tumor isolates.5 The precise mechanism of tumor targeting by CD8+ NKT cells has not been fully elucidated. Previous investigations demonstrated that target cell recognition involves the interaction of adhesion molecules, for example LFA-1/ICAM-1, and the stimulation of NKG2D, a member of the c-type lectin-activating receptor family.6 Following 3 weeks in culture, CD8+ NKT cells upregulate a number of effector molecules with perforin being the most relevant for mediating cellular cytotoxicity.

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Acknowledgements

We are grateful for technical assistance by Colette Huenefeld and statistical analysis by Dr Andreas Grote. This work was supported by IMF SC 110212, University of Muenster to CS. MP and CS contributed equally.

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Authors and Affiliations

  1. Department of Medicine/Hematology and Oncology, University of Muenster, Muenster, Germany

    M Pieper, C Scheffold, G Bisping, M Stelljes, W E Berdel & J Kienast

  2. Department of Pediatric Hematology and Oncology, University of Muenster, Muenster, Germany

    S Duwe, C Rossig & H Jurgens

  3. Department of Immunology, Duke University, Durham, NC, USA

    T F Tedder

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  1. M Pieper
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  2. C Scheffold
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  9. W E Berdel
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  10. J Kienast
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Correspondence to C Scheffold.

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Pieper, M., Scheffold, C., Duwe, S. et al. Immunotherapy of B-cell malignancies with genetically engineered human CD8+ natural killer T cells. Leukemia 20, 729–732 (2006). https://doi.org/10.1038/sj.leu.2404114

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