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

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Item Type:	Article
Title:	T cell receptor gene transfer exclusively to human CD8+ cells enhances tumor cell killing
Creators Name:	Zhou, Q., Schneider, I.C., Edes, I., Honegger, A., Bach, P., Schoenfeld, K., Schambach, A., Wels, W.S., Kneissl, S., 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
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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