Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells

A. Loskog, V. Giandomenico, C. Rossig, M. Pule, G. Dotti, M. K. Brenner

Research output: Contribution to journalArticle

135 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1819-1828
Number of pages10
JournalLeukemia
Volume20
Issue number10
DOIs
StatePublished - Oct 2006

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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