Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling
S Wilkie, MCI van Schalkwyk, S Hobbs… - Journal of clinical …, 2012 - Springer
S Wilkie, MCI van Schalkwyk, S Hobbs, DM Davies, SJC van der Stegen, ACP Pereira…
Journal of clinical immunology, 2012•SpringerPurpose 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 …
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 …
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.
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