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J Clin Immunol. 2012 Oct;32(5):1059-70. doi: 10.1007/s10875-012-9689-9. Epub 2012 Apr 17.

Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling.

Author information

1
King's College London, King's Health Partners Integrated Cancer Center, Department of Research Oncology, Guy's Hospital Campus, Great Maze Pond, London, SE1 9RT, UK.

Abstract

PURPOSE:

Chimeric antigen receptor (CAR) engineered T-cells occupy an increasing niche in cancer immunotherapy. In this context, CAR-mediated CD3ζ signaling is sufficient to elicit cytotoxicity and interferon-γ production while the additional provision of CD28-mediated signal 2 promotes T-cell proliferation and interleukin (IL)-2 production. This compartmentalisation of signaling opens the possibility that complementary CARs could be used to focus T-cell activation within the tumor microenvironment.

METHODS:

Here, we have tested this principle by co-expressing an ErbB2- and MUC1-specific CAR that signal using CD3ζ and CD28 respectively. Stoichiometric co-expression of transgenes was achieved using the SFG retroviral vector containing an intervening Thosea asigna peptide.

RESULTS:

We found that "dual-targeted" T-cells kill ErbB2(+) tumor cells efficiently and proliferate in a manner that requires co-expression of MUC1 and ErbB2 by target cells. Notably, however, IL-2 production was modest when compared to control CAR-engineered T-cells in which signaling is delivered by a fused CD28 + CD3ζ endodomain.

CONCLUSIONS:

These findings demonstrate the principle that dual targeting may be achieved using genetically targeted T-cells and pave the way for testing of this strategy in vivo.

PMID:
22526592
DOI:
10.1007/s10875-012-9689-9
[Indexed for MEDLINE]

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