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Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor

Nature Biotechnology volume 20, pages 70–75 (2002)Cite this article

Abstract

Artificial receptors provide a promising approach to target T lymphocytes to tumor antigens. However, the receptors described thus far produce either an activation or a co-stimulatory signal alone, thus limiting the spectrum of functions accomplished by the genetically modified cells. Here we show that human primary T lymphocytes expressing fusion receptors directed to prostate-specific membrane antigen (PSMA) and containing combined T-cell receptor-ζ (TCRζ), and CD28 signaling elements, effectively lyse tumor cells expressing PSMA. When stimulated by cell-surface PSMA, retrovirally transduced lymphocytes undergo robust proliferation, expanding by more than 2 logs in three weeks, and produce large amounts of interleukin-2 (IL-2). Importantly, the amplified cell populations retain their antigen-specific cytolytic activity. These data demonstrate that fusion receptors containing both TCR and CD28 signaling moieties are potent molecules able to redirect and amplify human T-cell responses. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of tumor cells that fail to express major histocompatibility complex antigens and co-stimulatory molecules.

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Figure 1: Structure of TCRζ–CD28 fusion receptors.
Figure 2: Expression of PSMA-specific TCRζ–CD28 fusion receptors in primary human T lymphocytes (PBLs).
Figure 3: Specific target cell lysis by PSMA-redirected T cells.
Figure 4: The P28z fusion receptor renders human T lymphocytes capable of PSMA-dependent expansion.
Figure 5: Primary and secondary stimulation of transduced T cells in response to PSMA.
Figure 6: PSMA+ tumor cells activate cytolytic and proliferative responses in P28z-transduced PBLs.

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Acknowledgements

We thank P. King and C. Lyddane for critical review of the manuscript. We also thank H. Gallardo and H. Zhu for assistance with T-cell transduction, and J.-B. Latouche for providing NIH3T3-derived feeder cells. This work was supported by the National Institutes of Health, grant CA-59350, the CaP CURE Association, the Jean Shanks Clinical Research Fellowship (Royal College of Pathologists, London, UK), and the Cure for Lymphoma Foundation.

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  1. Department of Human Genetics/Medicine, Gene Transfer and Somatic Cell Engineering Laboratory, and Immunology Program, Memorial Sloan–Kettering Cancer Center, New York, 10021, NY

    John Maher, Renier J. Brentjens, Gertrude Gunset, Isabelle Rivière & Michel Sadelain

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Correspondence to Michel Sadelain.

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Maher, J., Brentjens, R., Gunset, G. et al. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor. Nat Biotechnol 20, 70–75 (2002). https://doi.org/10.1038/nbt0102-70

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