Title: Optimising Radiation Therapy in Head and Neck Cancers Using Functional Image-Guided Radiotherapy and Immuno-oncology Agents
Funder: Cancer Research UK

Abstract: Background Locally-advanced head and neck cancer (LAHNC) is a major cause of cancer-related morbidity and mortality. Current standards-of-care frequently fail to cure the disease and cause appreciable early and late side-effects. Non-surgical approaches are based on radiotherapy, with or without concomitant drug treatment. Our previous programme, “Physical and biological optimisation of radiotherapy in head and neck cancer”, focussed on three themes: physically-targeted radiation dose-escalation; tumour-selective radiosensitisers targeting S-G2/M cell cycle checkpoints; and predicting radiation responses in tumour and normal tissues. Aims We propose to build on successes from our previous programme to deliver two specific research goals. We will: (i) develop functional image-guided radiotherapy (FIgRT) on the MR-Linac treatment platform to maximise tumour control and minimise normal tissue toxicity; and (ii) combine radiotherapy/chemoradiotherapy with immuno-oncology agents (IO) in preclinical and clinical models. Methods Our work on FIgRT will involve preclinical (subcutaneous and orthotopic) models and clinical studies. We will use functional MR parameters, initially from MR images acquired for treatment planning, but ultimately captured in real-time on the MR-Linac, to guide IGRT solutions for patients with LAHNC. We will focus on two key therapeutic aims: (i) dose-escalation to areas of biologically adverse disease (in HPV-negative and HPV-positive disease); and (ii) dose de-escalation in low-/intermediate-risk HPV-positive disease. Ultimately, we will integrate in vivo and imaging-based biomarkers of treatment response in a personalised, risk-based, algorithm to deliver adaptive treatment plans for patients with LAHNC. We will develop therapeutic strategies to combine IO agents with standard-of-care radiotherapy regimens (including platin- and taxane-based chemotherapy and DNA damage response inhibition). Specifically, we will focus on systemically-administered immune checkpoint-inhibiting monoclonal antibodies and direct injections of IO agents (Toll-like receptor (TLR) agonist, stimulator of interferon genes (STING) agonist, oncolytic immunotherapy) that can modify innate and adaptive immune responses. Our programme of preclinical and clinical studies will allow us to conduct detailed mechanistic analyses of combinations of radiotherapy/chemoradiotherapy with IO agents to define changes in immune cell infiltration, repertoire and functional activities and to analyse treatment-related changes in tumour neoantigens. How the results of this research will be used Our research will deliver more effective and less toxic radiotherapy-based treatments for patients and define the role of different classes of IO agents in the setting of radical, non-surgical curative treatment of LAHNC.


Research activity codes: 5.1 PHARMACEUTICALS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS