1. ¹Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
2. ²Rudbeck Laboratory, Clinical Immunology Division, Uppsala University, Uppsala, Sweden
3. ³Department of Paediatric Haematology and Oncology, University Children's Hospital Muenster, Muenster, Germany

Correspondence: Dr A Loskog, Rudbeck Laboratory, Clinical Immunology Division, Uppsala University, Dag Hammarskjoldsv 20, Uppsala 751 85, Sweden. E-mail: angelica.loskog@klinimm.uu.se

Received 21 March 2006; Revised 3 July 2006; Accepted 5 July 2006; Published online 17 August 2006.

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 () 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 -chain and CD19 single-chain Fv not only produced a higher proliferative response and an increased nuclear factor 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.