Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction

Fabio Turatti, Mariangela Figini, Emanuela Balladore, Paola Alberti, Patrizia Casalini, James D. Marks, Silvana Canevari, Delia Mezzanzanica

Research output: Contribution to journalArticlepeer-review

Abstract

Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the ζ-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.

Original languageEnglish
Pages (from-to)684-693
Number of pages10
JournalJournal of Immunotherapy
Volume30
Issue number7
DOIs
Publication statusPublished - Oct 2007

Keywords

  • Chimeric immune receptor
  • Cytotoxicity
  • Human T cells

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Immunology

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