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Genetic engineering of cytolytic T lymphocytes for adoptive T-cell therapy of neuroblastoma

✍ Scribed by Sergio Gonzalez; Araceli Naranjo; Lisa M. Serrano; Wen-Chung Chang; Christine L. Wright; Michael C. Jensen

Publisher
John Wiley and Sons
Year
2004
Tongue
English
Weight
151 KB
Volume
6
Category
Article
ISSN
1099-498X

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✦ Synopsis

Abstract

Background

Disease relapse is the leading cause of mortality for children diagnosed with disseminated neuroblastoma. The adoptive transfer of tumor‐specific T cells is an attractive approach to target minimal residual disease following conventional therapies. We describe here the genetic engineering of human cytotoxic T lymphocytes (CTL) to express a chimeric immunoreceptor for re‐directed HLA‐independent recognition of neuroblastoma.

Methods

The CE7R chimeric immunoreceptor was constructed by PCR splice overlap extension and is composed of a single‐chain antibody extracellular domain (scFv) derived from the L1‐CAM‐specific murine CE7 hybridoma fused to human IgG1 hinge‐Fc, the transmembrane portion of human CD4, and the cytoplasmic tail of huCD3‐ζ chain (scFvFc:ζ). Primary human T cells were genetically modified by naked DNA electrotransfer of plasmid expression vector CE7R‐pMG then analyzed by Western blotting, flow cytometry for CE7R expression and cell surface trafficking, 4‐h chromium release assay for re‐directed neuroblastoma lysis, and ELISA for tumor‐specific activation of cytokine production.

Results

CE7R is expressed as an intact chimeric protein that trafficks to the cell surface as a type I transmembrane protein. Primary human CE7R‐expressing CD8^+^ CTL clones specifically recognize human neuroblastoma tumor cells and are activated for tumor cell lysis and T~c~1 cytokine production.

Conclusions

These data demonstrate the utility of CE7R for re‐directing the effector function of CTL to neuroblastoma and have provided the rationale to initiate a FDA‐authorized (BB‐IND#9149) pilot clinical trial to establish the feasibility and safety of adoptive transfer of autologous CE7R^+^CD8^+^ CTL clones to children with recurrent/refractory neuroblastoma. Copyright © 2004 John Wiley & Sons, Ltd.

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