Original Manuscript
Leukemia (2004) 18, 676–684. doi:10.1038/sj.leu.2403302 Published online 12 February 2004
Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia
C Imai1, K Mihara1, M Andreansky1, I C Nicholson2, C-H Pui1,3,4, T L Geiger3 and D Campana1,3,4
- 1Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA
- 2Child Health Research Institute, Women's and Children's Hospital, Adelaide, South Australia
- 3Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA
- 4Department of Pediatrics, University of Tennessee College of Medicine, Memphis, TN, USA
Correspondence: Dr D Campana, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis TN 38105-2794, USA. Fax: +901-495 3749; E-mail: dario.campana@stjude.org
Received 31 December 2003; Accepted 5 January 2004; Published online 12 February 2004.
Abstract
To develop a therapy for drug-resistant B-lineage acute lymphoblastic leukemia (ALL), we transduced T lymphocytes with anti-CD19 chimeric receptors, consisting of an anti-CD19 single-chain variable domain (reactive with most ALL cases), the hinge and transmembrane domains of CD8
, and the signaling domain of CD3
. We compared the antileukemic activity mediated by a novel receptor ('anti-CD19-BB-') containing the signaling domain of 4-1BB (CD137; a crucial molecule for T-cell antitumor activity) to that of a receptor lacking costimulatory molecules. Retroviral transduction produced efficient and durable receptor expression in human T cells. Lymphocytes expressing anti-CD19-BB- receptors exerted powerful and specific cytotoxicity against ALL cells, which was superior to that of lymphocytes with receptors lacking 4-1BB. Anti-CD19-BB- lymphocytes were remarkably effective in cocultures with bone marrow mesenchymal cells, and against leukemic cells from patients with drug-resistant ALL: as few as 1% anti-CD19-BB--transduced T cells eliminated most ALL cells within 5 days. These cells also expanded and produced interleukin-2 in response to ALL cells at much higher rates than those of lymphocytes expressing equivalent receptors lacking 4-1BB. We conclude that anti-CD19 chimeric receptors containing 4-1BB are a powerful new tool for T-cell therapy of B-lineage ALL and other CD19+ B-lymphoid malignancies.
Keywords:
T-cell receptor, CD137, acute lymphoblastic leukemia, B-cell lymphoma
