Assessment of CCR5/Maraviroc immunotherapy in combination with PD1 and MR-Guided radiotherapy for treatment of pancreatic cancer


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Simone Lanfredini1,Sophie Hughes2,Asmita Thapa2,Fiona Bangs2,Jennifer Morton3,Helen Ferry2,Veerle Kersemans2,Paul Kinchesh2,Sean Smart2,Amily Elliot2,James Thompson2,Mark Hill2,Somnath Mukherjee2,Eric O'Neill2
1Oxford University,2University of Oxford,3University of Glasgow

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC), is the most prevalent form of pancreatic cancers with poor survival outcomes. Results from the clinic have demonstrated the lack of efficacy when either radiotherapy (RT) or immunotherapy are used as a monotherapy. Recent publications revealed a synergistic effect on RT-induced immune-modulation and reduced immune-suppression when the immunotherapy was administrated concurrently with RT in mouse models. Other publications demonstrate that immune-evasion in PDAC depends on the CCL5/CCR5 axis to recruit immunosuppressive T-regulatory cells (Tregs) into the tumour microenvironment. Therefore, targeting the migration of Tregs through modulation of CCL5/CCR5 axis can potentially inhibit tumour growth in pancreatic cancer.

Aim:Working within the Precision Panc platform, this pre-clinical study is evaluating the impact of fractionated MR-guided radiotherapy in combination CCR5 inhibitor and simultaneous inhibition of the immune checkpoint axis PD1/PD-L1.

Method

For the purpose of this study we generated a syngeneic orthotopic pancreatic mouse model. Tumour cells derived from the Lox-Stop-Lox (LSL)-KrasG12D; LSL-Trp53R172H; Pdx1-cre (KPC) mouse model, are injected in the tail of the pancreas. We are able to monitor tumour growth using a respiratory motion desensitised T2-weighted MRI imager. Taking advantage of in-house developed technology, we use the SARRP in combination with MRI imaging to deliver MR-guided fractionated radiotherapy in combination with CCR5 inhibitor (Maraviroc) and PD1 inhibitor. To investigate the immunological microenvironment, we developed a 17-colour flow cytometry (FC) panel to immune-phenotype cytotoxic T, T regulatory, NK, NK/T and B cells, M-MDSC, PMN-MDSC, M1 and M2 macrophages in the peripheral blood and tumour infiltrate

Results

Outcome data will be presented at the meeting.

Conclusion

Using the established orthotopic mouse model our aim is to investigate how the combination of MRI-guided radiotherapy and immune therapies can modulate the tumour microenvironment and the immune response in pancreatic cancer.