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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2643-2652.
Prepublished online as a Blood First Edition Paper on December 13, 2005; DOI 10.1182/blood-2005-09-3904.
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GENE THERAPY
Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy
Lisa Marie Serrano,
Timothy Pfeiffer,
Simon Olivares,
Tontanai Numbenjapon,
Jennifer Bennitt,
Daniel Kim,
David Smith,
George McNamara,
Zaid Al-Kadhimi,
Joseph Rosenthal,
Stephen J. Forman,
Michael C. Jensen, and
Laurence J. N. Cooper
From the Beckman Research Institute and City of Hope National Medical Center Division of Molecular Medicine, Division of Cancer Immunotherapeutics and Tumor Immunology, Division of Hematology and Hematopoietic Cell Transplantation, Division of Pediatric Oncology, and the Division of Biomedical Informatics, Durate, CA.
Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)–derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.
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