Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia

C. Imai, K. Mihara, M. Andreansky, I. C. Nicholson, C. H. Pui, T. L. Geiger, Dario Campana

Research output: Contribution to journalArticle

360 Scopus citations

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 CD8α, and the signaling domain of CD3ζ. We compared the antileukemic activity mediated by a novel receptor ('anti-CD19-BB-ζ') 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-ζ receptors exerted powerful and specific cytotoxicity against ALL cells, which was superior to that of lymphocytes with receptors lacking 4-1BB. Anti-CD19-BB-ζ 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-ζ-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.

Original languageEnglish (US)
Pages (from-to)676-684
Number of pages9
JournalLeukemia
Volume18
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

Keywords

  • Acute lymphoblastic leukemia
  • B-cell lymphoma
  • CD137
  • T-cell receptor

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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