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

研究成果: Article査読

452 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)676-684
ページ数9
ジャーナルLeukemia
18
4
DOI
出版ステータスPublished - 04-2004
外部発表はい

All Science Journal Classification (ASJC) codes

  • 血液学
  • 腫瘍学
  • 癌研究

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