Enabling immunotherapy through the detection and sequestration of CO by fluorogenic probes

This project aims to develop a new family of water-compatible probes that are able to fluorogenically detect the small amounts of carbon monoxide (CO) produced endogenously in cells and in the body. This production is largely due to the catabolism of haem by haem oxygenase (HO-1) and the inhibition of this enzyme is associated with better chemotherapy outcomes in humans. These probes will be used to interrogate the effect of CO in suppressing the immune response towards tumours, allowing the visualisation of this small molecule in vitro and in vivo. Translation of this approach into the clinic could allow the estimation of CO production as a function of HO-1 expression to be used to gauge the likely response of patients towards chemotherapy as part of an assisted immune response.

Cancer immunotherapy harnesses the immune system to attack and eradicate cancer. For this to be achieved, the mechanisms which are exploited within the tumour microenvironment to suppress immune responses need to be investigated and optical methods (e.g., fluorescence imaging) are well-suited to study this. Tumoural immune suppression is a major hurdle to permitting effective cancer immunotherapy in the clinic (Arnold, Ng et al, Nature Comm. 2018, 9, 1). The enzyme haem oxygenase-1 (HO-1), which is expressed in a variety of tumours, generates carbon monoxide (CO) in its enzymatic degradation of the molecule haem. Alongside many other regulatory cellular roles as a gasotransmitter, CO is immune suppressive and can compromise T-cell responses in the tumour microenvironment, preventing cytolytic killing of the tumour. However, the detection and real-time tracking of CO in cells and in vivo requires probes that are synthetically-straightforward, robust, non-cytotoxic as well as being highly sensitive and selective for CO.

The Wilton-Ely (JWE) group has developed a series of probes based on ruthenium and osmium for the selective detection of CO in air (J. Am. Chem. Soc. 2014, 136, 11930) and in cells (J. Am. Chem. Soc. 2017, 139, 18484). The detection system is based on the extremely high affinity of carbon monoxide ligand for the metal centre, leading to rapid and selective binding and very low detection limits (1 ppb). These complexes show excellent stability and are not cytoxic. This has been illustrated in the monitoring of in vivo production of endogenous CO in response to inflammation in a realistic (subcutaneous air pouch) mouse model (J. Am. Chem. Soc. 2017, 139, 18484). However, new probe designs are needed, which have improved solubility and emission properties and can target particular features in the cells (e.g., mitochondria), associated with CO generation.

The PhD project will involve ligand synthesis, coordination chemistry, tissue culture, fluorescence measurements in cells and translation to animal models (with Dr James Arnold, Tumour Immunology Group, KCL).

Strains on the healthcare system in the UK create an acute need for finding more effective, efficient, safe, and accurate non-invasive imaging solutions for clinical decision-making, both in terms of diagnosis and prognosis, and to reduce unnecessary treatment procedures and associated costs. Medical imaging is currently undergoing a step-change facilitated through the advent of artificial intelligence (AI) techniques, in particular deep learning and statistical machine learning, the development of targeted molecular imaging probes and novel "push-button" imaging techniques. There is also the availability of low-cost imaging solutions, creating unique opportunities to improve sensitivity and specificity of treatment options leading to better patient outcome, improved clinical workflow and healthcare economics. However, a skills gap exists between these disciplines which this CDT is aiming to fill.

Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.

- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.

- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.

- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.

We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.