A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity

De Gang Song, Qunrui Ye, Mathilde Poussin, Lin Liu, Mariangela Figini, Daniel J. Powell

Research output: Contribution to journalArticlepeer-review

Abstract

Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate "on-target" toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (αFR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with αFR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based αFR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for αFR protein and exhibited reduced recognition of normal cells expressing low levels of αFR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and "ontarget off-tumor" toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs.

Original languageEnglish
Pages (from-to)21533-21546
Number of pages14
JournalOncotarget
Volume6
Issue number25
Publication statusPublished - 2015

Keywords

  • Adoptive immunotherapy
  • Chimeric antigen receptor
  • Folate receptor alpha
  • Ovarian cancer
  • T cells

ASJC Scopus subject areas

  • Oncology

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