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Background
Recent evidence suggests that the co-inhibitory PD-1-PD-L1 axis plays a major role
in adoptive T cell therapy failure. We hypothesised that a new fusion receptor reverting
PD-1-mediated inhibition into CD28-costimulation may brake peripheral tolerance.
Methods
Different PD-1-CD28 fusion receptor constructs were created and retrovirally transduced
into primary, ovalbumine specific CD8+ T cells (OT-1). Cytokine release, proliferation,
cytotoxicity and tumour recognition were analysed in vitro. Anti-tumour efficacy and
mode of action were investigated in mice bearing subcutaneous Panc-OVA tumours.
Results
Transduction of the PD-1-CD28 receptor constructs mediated enhanced cytokine-release,
pronounced T cell proliferation and T cell-induced lysis of target tumour cells upon
PD-L1 engagement. The PD-1-CD28 receptor function was dependent on two of the CD28-signalling
motifs and interferon (IFN)-γ release. Treatment of mice with established Panc-OVA tumours with fusion receptor-transduced
OT-1 T cells mediated complete tumour regression in 83% of mice. Mice rejecting the
tumour were protected upon subsequent rechallenge with either ovalbumin positive or
negative tumours, indicative of a memory response and epitope spreading. Treatment
efficacy was associated with accumulation of IFN-γ producing T cells in the tumours.
Conclusions
Transduction of T cells with this new receptor has the potential of braking the PD-1-PD-L1
immunosuppressive axis in ACT.
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