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

Authors

  • Q. Zhou
  • I.C. Schneider
  • I. Edes
  • A. Honegger
  • P. Bach
  • K. Schoenfeld
  • A. Schambach
  • W.S. Wels
  • S. Kneissl
  • W. Uckert
  • C.J. Buchholz

Journal

  • Blood

Citation

  • Blood 120 (22): 4334-4342

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.


DOI

doi:10.1182/blood-2012-02-412973