Abstract
T cells can be engineered to target tumor cells by transduction of tumor-specific chimeric receptors, consisting of an extracellular antigen-binding domain and an intracellular signaling domain. However, the peripheral blood of cancer patients frequently contains an increased number of T regulatory cells, which appear to inhibit immune reactivity. We have investigated the effects of T regulatory cells on chimeric T cells specific for the B-cell antigen CD19, as B-cell malignancies are attractive targets for chimeric T-cell therapy. When a CD19 single-chain Fv antibody was coupled to the CD3 zeta (ζ) chain, there was sharply reduced activity on exposure to T regulatory cells, measured by CD19+ target-induced proliferation and cytotoxicity. By contrast, expression in T cells of a chimeric receptor consisting of the intracellular portion of the CD28 molecule fused to the ζ-chain and CD19 single-chain Fv not only produced a higher proliferative response and an increased nuclear factor κB activation but also sustained these activities in the presence of T regulatory cells. These effects are seen whether the chimeric T cells are derived from normal donors or from patients with B-cell chronic lymphocytic leukemia, indicating the potential for clinical application in B cell malignancies.
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Acknowledgements
We thank Dr Ettore Biagi, Eric Yvon and Dr Barbara Savoldo for B-CLL patient material and excellent technical advice (Baylor College of Medicine, Houston, TX, USA). This work was supported by NIH Grant CA94237 and grants from Emil and Ragna Börjessons Memory Fund, the Swedish Cancer Fund and Uppsala University Hospital Funds.
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Loskog, A., Giandomenico, V., Rossig, C. et al. Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells. Leukemia 20, 1819–1828 (2006). https://doi.org/10.1038/sj.leu.2404366
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DOI: https://doi.org/10.1038/sj.leu.2404366
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