Adoptive transfer of cytotoxic T lymphocytes targeting two different antigens limits antigen loss and tumor escape.

Karen M. Kaluza, Timothy Kottke, Rosa Maria Diaz, Diana Rommelfanger, Jill Thompson, Richard Vile

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

An antitumor T-cell response can lead to tumor control without clearing all tumor cells. As long as residual tumor cells remain, there is a constant risk of escape from that T-cell response. We previously showed that adoptive transfer of anti-ova OT-I T cells into B16ova-bearing mice led to tumor regression followed by escape of tumors that had lost the ova gene, rendering the OT-I T cells ineffective. In this study, we hypothesized that simultaneous transfer of cytotoxic T lymphocytes targeted against two independent antigens would reduce selection for single-antigen-loss cells, thereby limiting tumor escape. Using OT-I and Pmel T cells to treat B16ova tumors, we found that early cotransfer could prevent tumor emergence in most mice, whereas neither T-cell specificity alone was able to do so. When combined with total body irradiation for the treatment of larger 7-day tumors, cotransfer was also better at limiting tumor recurrence, and the tumors that did escape combination therapy continued to express both target antigens. As adoptively transferred T cells also persisted in vivo, even in mice with recurrent tumors, we hypothesized that restimulation of these antitumor T cells would prolong survival of mice with recurrent tumors. Consistent with this hypothesis, administration of a low-dose regimen of cyclophosphamide following tumor escape slowed tumor growth in mice that had previously received T-cell therapy, but not in control-treated mice, an effect that was associated with increased activation of T cells in vitro by low- but not high-dose cyclophosphamide.

Original languageEnglish (US)
Pages (from-to)1054-1064
Number of pages11
JournalHuman gene therapy
Volume23
Issue number10
DOIs
StatePublished - Oct 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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