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T cell receptor gene transfer exclusively to human CD8+ cells enhances tumor cell killing

Item Type:Article
Title:T cell receptor gene transfer exclusively to human CD8+ cells enhances tumor cell killing
Creators Name:Zhou, Q. and Schneider, I.C. and Edes, I. and Honegger, A. and Bach, P. and Schoenfeld, K. and Schambach, A. and Wels, W.S. and Kneissl, S. and Uckert, W. and Buchholz, C.J.
Abstract:Transfer of tumor-specific T cell receptor (TCR) genes into patient T cells is a promising strategy in cancer immunotherapy. We describe here a novel vector (CD8-LV) derived from lentivirus, which delivers genes exclusively and specifically to CD8(+) cells. CD8-LV mediated stable in vitro and in vivo reporter gene transfer as well as efficient transfer of genes encoding TCRs recognizing the melanoma antigen tyrosinase. Strikingly, T cells genetically modified with CD8-LV killed melanoma cells reproducibly more efficiently than CD8(+) cells transduced with a conventional lentiviral vector. Neither TCR expression levels, nor the rate of activation-induced death of transduced cells differed between both vector types. Instead, CD8-LV transduced cells showed increased granzyme B and perforin levels as well as an upregulation of CD8 surface expression in a small subpopulation of cells. Thus, a possible mechanism for CD8-LV enhanced tumor cell killing may be based on activation of the effector functions of CD8(+) T cells by the vector particle displaying OKT8-derived CD8-scFv and an increase of the surface density of CD8, which functions as co-receptor for tumor cell recognition. CD8-LV represents a powerful novel vector for TCR gene therapy and other applications in immunotherapy and basic research requiring CD8(+) cell-specific gene delivery.
Keywords:Adoptive Immunotherapy, Biological Models, CD8-Positive T-Lymphocytes, Cultured Cells, Gene Transfer Techniques, Genetic Therapy, HEK293 Cells, Immunologic Cytotoxicity, Inbred NOD Mice, Jurkat Cells, Neoplasms, Organ Specificity, SCID Mice, T-Cell Antigen Receptors, Up-Regulation, Xenograft Model Antitumor Assays, Animals, Mice
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Volume:120
Number:22
Page Range:4334-4342
Date:22 November 2012
Official Publication:https://doi.org/10.1182/blood-2012-02-412973
PubMed:View item in PubMed

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