TY - JOUR
T1 - Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells
AU - Loskog, A.
AU - Giandomenico, V.
AU - Rossig, C.
AU - Pule, M.
AU - Dotti, G.
AU - Brenner, M. K.
PY - 2006/10
Y1 - 2006/10
N2 - 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.
AB - 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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U2 - 10.1038/sj.leu.2404366
DO - 10.1038/sj.leu.2404366
M3 - Article
C2 - 16932339
AN - SCOPUS:33750061330
VL - 20
SP - 1819
EP - 1828
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 10
ER -