Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells
2006 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 20, no 10, 1819-1828 p.Article in journal (Refereed) Published
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 ( zeta) 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 zeta-chain and CD19 single-chain Fv not only produced a higher proliferative response and an increased nuclear factor kappa B 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.
Place, publisher, year, edition, pages
2006. Vol. 20, no 10, 1819-1828 p.
chimeric T cells, CD28, T regulatory cells, CD19, B-CLL
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-25752DOI: 10.1038/sj.leu.2404366ISI: 000241381000022PubMedID: 16932339OAI: oai:DiVA.org:uu-25752DiVA: diva2:53526