Conversion of a tumor-binding peptide identified by phage display to a functional chimeric T cell antigen receptor

C. R.J. Pameijer, A. Navanjo, B. Meechoovet, J. R. Wagner, B. Aguilar, C. L. Wright, W. C. Chang, C. E. Brown, M. C. Jensen

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Adoptive transfer of ex vivo expanded tumor-specific T cells is a promising therapeutic modality for promoting or augmenting antitumor immunity. Several groups, including ours, are developing antigen receptor gene transfer strategies as a means of generating effector cells for adoptive therapy. Chimeric antigen receptors (CARs) have been described that use single-chain antibodies or cytokine ligands as tumor targeting domains. Here, we describe the capacity of a tumor-binding peptide identified by phage display combinatorial library screening to serve as a CAR targeting domain. A phage library-selected high-affinity 12-mer peptide (Bpep) specific for alpha(v) beta(6) integrin (αvβ6) was chosen for these studies. Primary human T cells were genetically modified to express the Bpep-CAR consisting of an αvβ6-specific peptide and human IgG4 hinge-Fc extracellular domain fused to the cytoplasmic tail of CD3-ζ. T cell expression of the Bpep-CAR was assessed by Western blot analysis, and trafficking of the Bpep-CAR to the cell surface was demonstrated by flow cytometry. Functionally, Bpep-CAR redirected cytotoxic T lymphocytes specifically kill integrin αvβ6+ ovarian tumor targets, and are activated for interferon gamma secretion. Our data suggest that large new repertoires of tumor-specific T cell antigen receptor transgenes might be available through merging combinatorial peptide libraries with CAR construct design.

Original languageEnglish (US)
Pages (from-to)91-97
Number of pages7
JournalCancer gene therapy
Volume14
Issue number1
DOIs
StatePublished - Jan 22 2007

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

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