T-cell receptor gene therapy of established tumors in a murine melanoma model

John D Abad, Claudia Wrzensinski, Willem Overwijk, Moniek A De Witte, Annelies Jorritsma-Smit, Cary Hsu, Luca Gattinoni, Cyrille J Cohen, Chrystal M Paulos, Douglas C Palmer, John B A G Haanen, Ton N M Schumacher, Steven A Rosenberg, Nicholas P Restifo, Richard A. Morgan

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Adoptive cell transfer therapy using tumor-infiltrating lymphocytes for patients with metastatic melanoma has demonstrated significant objective response rates. One major limitation of these current therapies is the frequent inability to isolate tumor-reactive lymphocytes for treatment. Genetic engineering of peripheral blood lymphocytes with retroviral vectors encoding tumor antigen-specific T-cell receptors (TCRs) bypasses this restriction. To evaluate the efficacy of TCR gene therapy, a murine treatment model was developed. A retroviral vector was constructed encoding the pmel-1 TCR genes targeting the B16 melanoma antigen, gp100. Transduction of C57BL/6 lymphocytes resulted in efficient pmel-1 TCR expression. Lymphocytes transduced with this retrovirus specifically recognized gp100-pulsed target cells as measured by interferon-gamma secretion assays. Upon transfer into B16 tumor-bearing mice, the genetically engineered lymphocytes significantly slowed tumor development. The effectiveness of tumor treatment was directly correlated with the number of TCR-engineered T cells administered. These results demonstrated that TCR gene therapy targeting a native tumor antigen significantly delayed the growth of established tumors. When C57BL/6 lymphocytes were added to antigen-reactive pmel-1 T cells, a reduction in the ability of pmel-1 T cell to treat B16 melanomas was seen, suggesting that untransduced cells may be deleterious to TCR gene therapy. This model may be a powerful tool for evaluating future TCR gene transfer-based strategies.

Original languageEnglish
Pages (from-to)1-6
Number of pages6
JournalHuman vaccines & immunotherapeutics
Volume31
Issue number1
DOIs
Publication statusPublished - Jan 2008

Keywords

  • Animals
  • CD8-Positive T-Lymphocytes
  • Cell Line, Tumor
  • Coculture Techniques
  • Genetic Therapy
  • Genetic Vectors
  • Immunophenotyping
  • Immunotherapy, Adoptive
  • Interferon-gamma
  • Lymphocyte Activation
  • Lymphocytes
  • Melanoma, Experimental
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, alpha-beta
  • Spleen
  • Transfection
  • gp100 Melanoma Antigen
  • Journal Article
  • Research Support, N.I.H., Intramural

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