Exploring an oncolytic virus triggered PD-L1 response via immunoPET
Thesis or Dissertation
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Oncolytic virotherapy (OV) exploits viruses which preferentially infect and kill cancerous cells. Moreover, oncolytic viruses stimulate the tumour-immune microenvironment towards an inflammatory phenotype. Therefore, OV is an attractive tool to prime tumours for clinically approved immunotherapies, such as immune checkpoint blockade (ICB). The latter is particularly relevant when ICB alone only moderately improves the therapy outcome over conventional treatment approaches, as observed in head and neck cancer. However, the impact of OV on the expression of programmed death-ligand 1 (PD-L1), a key target of ICB, remains vastly unexplored. Importantly, PD-L1 is expressed across multiple cell types and is sensitive towards various parameters in response to OV. In my PhD project I employed immuno-positron emission tomography (immunoPET) to explore the impact of OV on PD-L1 expression in syngeneic head and neck cancer mouse models (MOC1, MOC2). At first, I established an imaging protocol using a PD-L1 targeted PET tracer, 89Zr-DFO-PD-L1mAb, in mice bearing subcutaneous tumours with varying PD-L1 expression levels. Using this imaging protocol, I investigated the systemic changes of PD-L1 following local injection of the oncolytic herpesvirus RP1 to MOC tumours. The MOC1 model was selected based on its sensitivity to RP1 in vitro. Remarkably, a single dose of locally delivered RP1 induced a transient systemic increase of PD-L1 early after treatment, which was most pronounced in secondary lymphatic tissue. Surprisingly, these changes could not be linked to distinct serum cytokines. Ex vivo histopathology indicated an influx of immune effector cells, however no therapeutic benefit was achieved through an OV-ICB combination. In summary, PD-L1 immunoPET revealed that a single intratumoural dose of RP1 induces a systemic increase in PD-L1, highlighting that the immune-modulatory effect of this therapeutic approach reaches far beyond the tumour itself.
Preclin Molecular Imaging
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Institute of Cancer Research (University Of London)