Highly efficient redirected anti-tumor activity of human lymphocytes transduced with a completely human chimeric immune receptor

Fabio Turatti, Mariangela Figini, Paola Alberti, Ralph A. Willemsen, Silvana Canevari, Delia Mezzanzanica

Research output: Contribution to journalArticlepeer-review


Background: Novel antibody-based immunotherapeutic strategies exploit chimeric immune receptors (CIR), expressed on the surface of transduced human peripheral blood mononuclear cells (PBMC), to redirect potent non-0MHC-dependent cytotoxicity to tumor cells expressing a tumor-associated antigen. However, clinical application of the strategy has been hampered by the potential side effects associated with immunogenicity and by low transduction efficiency. Methods: A fully human CIR was constructed that triggers immune activation through the ζ chain of CD3 and contains a human single-chain antibody fragment specific for an extracellular epitope of HER2. PBMC were transduced with the CIR using gibbon-ape leukemia virus envelope pseudotyped retroviruses. In vitro cytotoxicity and inhibition assays were carried out using normal and tumor cell lines expressing different levels of HER2. Results: Bulk populations of CIR-transduced PBMC could express high levels of the construct and subcloning ensured stable expression. CIR-mediated killing and growth inhibition of targets expressing high HER2 levels were very efficient at low effector-to-target ratios. Under the same experimental conditions, CIR-mediated activity against normal cells expressing low HER2 levels was marginal. The CIR-mediated recognition of target cells induced the release of soluble factors able to inhibit growth of both HER-positive and HER2-negative bystander tumor cells. Conclusions: Human CIR-transduced PBMC exert a potent and dose-dependent anti-tumor activity. Target antigen level appeared to be a critical determinant of specificity and delivery of signals leading to redirected effector functions. Soluble factors, released by redirected effectors at the site of antigen-driven activation, mediate potent bystander killing.

Original languageEnglish
Pages (from-to)158-170
Number of pages13
JournalJournal of Gene Medicine
Issue number2
Publication statusPublished - Feb 2005


  • Bystander effect
  • Chimeric immune receptor
  • HER2 antigen
  • Lymphocyte transduction

ASJC Scopus subject areas

  • Genetics

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