About the Project
Background
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer world-wide. Patients with locally advanced HNSCC are usually treated with (i) radiotherapy with or without concurrent chemotherapy or with (ii) surgery with or without radio/chemotherapy. The only molecularly-targeted therapy used in HNSCC is cetuximab, an anti-EGFR antibody, which is used in combination with primary radiotherapy. For HNSCC patients who undergo radical radiotherapy, [18F]FDG PET scanning is performed to assess complete metabolic response.
Around 40% of HNSCC patients treated by radiotherapy are aged over 70. As the survival benefit decreases with increasing age, they are offered radiotherapy only. Also many oncologists would not offer concurrent cetuximab with radiotherapy for older patients because of concern about increased skin toxicities. There is currently a need to develop new treatment strategies to improve the outcome for locally-advanced HNSCC patients, in particular those who would otherwise receive radiotherapy alone due to their age or if platinum-based chemotherapy is deemed inappropriate.
Studies have demonstrated a critical role for immune cells in mediating response to radiotherapy. Irradiation has been shown to upregulate PD-L1 expression in the tumour microenvironment, specifically on dendritic cells, macrophages and tumour cells. The combination of anti-PD-L1 antibody with radiotherapy enhances radiotherapy response by for instance increasing CD8+ T cell response. Therefore, anti-PD-L1 antibody may enhance radiotherapy response in patients not suitable for concurrent chemoradiation or cetuximab with radiotherapy.
However, there is uncertainty of how to combine anti-PD-L1 with radiotherapy in terms of dose, fractionation and scheduling between radiotherapy and anti-PD-L1. Preclinical experiments are still required to guide future clinical trials.
Hypotheses
1. In HNSCC, treatment schedule is important and therapeutic efficacy would be better when radiotherapy is given concurrently with anti-PD-L1 antibody rather than sequentially.
2. Radiolabeled anti-PDL1 will enable us to predict response to combination therapies involving PD-L1 and radiotherapy.
Project
This project is highly interdisciplinary and uniquely combines radiobiological studies with radionuclide molecular imaging techniques, including preclinical precision radiotherapy that best mimics clinical radiotherapy. Changes in PD-L1 expression after various radiotherapy doses and scheduling will be studied in head and neck cancer cell lines. In vitro and in vivo studies will demonstrate whether concurrent anti-PD-L1 antibody with radiation will be more effective than sequential therapies. Ex vivo studies will be carried out to demonstrate whether results from proliferation markers, PD-L1 expression and immune infiltrates support observations seen in tumour growth. Radionuclide PET, non-invasive, whole body imaging studies will be carried out with [18F]F-FDG and a radiolabeled anti-PDL1 imaging tracer will be created to monitor early response to therapies. The project student will work closely with supervisors as well as clinical lead Dr Kong (Guy’s and St Thomas) to ensure clinical translation of the work and Dr Sosabowski (QMUL; radiolabeling antibodies).
Suitable candidates for this project will have a degree in Biomedical / Biological Sciences or subjects related to radionuclide imaging; minimum BSc, preferably MSc. Prior work experience in a research lab or industry will be considered favourably as will experience with animal work. For further details on how to apply please visit the CRUK CoL Centre RadNet studentships page: https://www.colcc.ac.uk/radnet-training-programme/
Potential research placements
1. Radiation biology: training of radiobiology of external beam radiation. Dr Terry, King’s College London and Anthony Kong, Guy’s and St Thomas’ Hospital
2. In vivo Tumour Radiation Application: training on the use of the Xstrahl SARRP small animal radiation research platform, Dr Kalber, UCL
3. Radiation Chemistry: training on radiochemistry techniques for antibody radiolabeling, Dr Sosabowski, QMUL
References
1. Terry, S.Y.A. et al. Call to arms: need for radiobiology in molecular radionuclide therapy. Eur J Nucl Med Mol Imaging; 2019, 46(8):1588-1590
2. Lobeek, D. et al. In vivo characterization of four 68Ga-labeled multimeric RGD peptides to image αvβ3 integrin expression in two human tumor xenograft mouse models. J Nucl Med; 2018, 59(8):1296-1301.
3. Terry, S.Y.A. et al. Can 111In-RGD2 monitor response to therapy in head and neck tumour xenografts? J Nucl Med; 2014, 55:1849-55.
4. Patrick, P.S. et al. Surface radio-mineralisation mediates chelate-free radiolabelling of iron oxide nanoparticles. Chem Sci; 2019, 10(9):2592-2597.
5. Weitsman, G. et al. Detecting intratumoral heterogeneity of EGFR activity by liposome-based in vivo transfection of a fluorescent biosensor. Oncogene; 2017, 36(25):3618-3628.
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