Investigating the multi-modality anti-tumour effects of combined sequential tumour irradiation and vascular-targeted photodynamic therapy in preclinical prostate cancer.


Year:

Session type:

Richard Bryant1, Hanna Sjoberg2, Yiannis Philippou2, Anette Magnussen2, Iain Tullis2, Esther Bridges2, Andrea Chatrian1, Joel Lefebvre1, Ka Ho Tam1, Emma Murphy2, Jens Rittscher1, Dina Preise3, Lilach Agemy3, Tamar Yechezkel3, Sean Smart2, Danny Allen2, David Scheiblin4, Stephen Lockett4, David Wink4, Alastair Lamb2, Ian Mills2, Adrian Harris2, Ruth Muschel2, Boris Vojnovic2, Avigdor Scherz3, Freddie Hamdy2
1University of Oxford, 2Cancer Research UK (CRUK) Oxford Centre, 3Weizmann Institute of Science, 4National Institutes of Health (NIH)

Abstract

Background

There is a need to improve treatment of prostate cancer (PCa), with fewer treatment-related side effects. Vascular-targeted photodynamic therapy (VTP) is a novel precision surgery focal ablation therapy, which rapidly disrupts targeted tumour vessels. VTP has been investigated as focal therapy for low-risk PCa, but its use has to date not been expanded to high risk disease, or as multi-modality therapy. The tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. Fractionated radiotherapy (FRT) is known to alter the tumour microenvironment to promote transient ‘vascular normalisation’. We tested the hypothesis that multi-modality therapy, combining FRT and VTP, could improve PCa tumour control, compared against monotherapy with FRT or VTP alone.

Method

TRAMP-C1 PCa flank tumour allografts were generated in vivo on an immunocompetent C57BL/6 background. We investigated whether sequential delivery of 3x5 Gy FRT followed by VTP (at 7-9 mg/kg WST-11) 7 days later improved tumour control compared to monotherapy with FRT or VTP alone. We also investigated the anti-tumour effects of VTP 7-9 mg/kg delivered during a course of concomitant 3x5 Gy FRT.

Results

FRT induced ‘vascular normalisation’ changes in PCa flank tumour allografts, as demonstrated using image analysis of CD31-positive blood vessels and αSMA-positive pericytes. FRT improved vascular function and tumour perfusion, as demonstrated using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). FRT followed 7 days later by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP, and improved overall survival. VTP delivered during concomitant FRT was no more effective than FRT or VTP monotherapy, and less effective than VTP delivered 7 days following FRT.

Conclusion

Taken together, this pre-clinical data suggests that sequentially combining FRT and novel focal ablation precision surgery VTP may be a promising multimodal approach in high risk PCa therapy. Further research aims to identify potential mechanisms of co-operation between these two treatments, with the aim of harnessing anti-tumour immunological responses.

Impact statement

This pre-clinical data provides first proof-of-concept for this multi-modality treatment, and may help to inform the design of future early phase clinical trials.