T-cell receptor gene transfer exclusively to human CD8(+) cells enhances tumor cell killing.
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 up-regulation 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 coreceptor 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.
Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany.
Qi
Q
Zhou
Irene C
IC
Schneider
Inan
I
Edes
Annemarie
A
Honegger
Patricia
P
Bach
Kurt
K
Schönfeld
Axel
A
Schambach
Winfried S
WS
Wels
Sabrina
S
Kneissl
Wolfgang
W
Uckert
Christian J
CJ
Buchholz
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D019169:Jurkat Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D009928:Organ Specificity / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D011948:Receptors, Antigen, T-Cell