Understanding the effects of combined immune checkpoint inhibition through space and time
Lead supervisor: Prof. David Withers
Co-supervisor: Prof. Simon Leedham, Prof. Ignacio Melero
Commercial partner: AstraZeneca
Despite the clinical success of targeting CTLA-4 or the PD-1: PD-L1 pathway in some cancer types, precisely how these treatments reshape the immune landscape of tumours remains incompletely understood. Only 10-30% of patients typically respond to these treatments when given alone, and in most cases, this does not result in protective immunity. Thus, there remains substantial scope and need to further refine these interventions. Combined targeting of these pathways enhances the anti-tumour response, but also the risk of life-threatening side effects. This highlights the need to precisely understand the mechanisms through which these intervention work and to validate this research using robust in vivo models.
Here, we will provide detailed new insight into how combined targeting of CTLA-4 and PD-1 changes the anti-tumour response, dissecting the tissue sites (i.e., the SPACE) in which different cellular changes are wrought by treatment, and how this alters the progression of the response and changes immune cell fate (over TIME). This research fully aligns to the MRC aim of exploring the mechanisms of existing and new therapeutics in cancer. Crucially, through working closely with researchers at AstraZeneca, with whom an excellent relationship has been developed over many years of collaboration, this proposal sits at the interface of fundamental and translational research. Insight from experienced researchers within AstraZeneca, ensures a clear focus on addressing the current challenges with licensed treatments. Combining this with the basic research of leading cancer immunologists, enables cutting-edge research tools to be exploited and new opportunities to enhance anti-tumour immunity unlocked.
To achieve this, whole tissue photoconversion will be utilised, an in vivo approach pioneered within the Withers Lab, that enables site-specific (photo)labelling of cells within defined microenvironments at a given time. This methodology can be used to interrogate cellular changes over time specifically within the tumour versus draining lymphoid tissue. Precise tracking of cellular movement between different tissues, will reveal new insight into the dissemination of memory T cells and how protective immunity may develop in response to treatment. The project will utilise an array of established mouse tumour models of varying complexity, balancing detailed immunological insight with the most physiological models of human cancers, with a focus on colorectal cancer. Other genetically engineered in vivo models targeting specific cell types or molecules will further maximise the mechanistic insight obtained.
Specifically, we will interrogate:
1. The mechanistic contribution of CTLA-4 and PD-1 inhibition alone and in combination on immune cells resident in the draining lymph node and tumour and how these cells interact across these tissues.
2) How dose scheduling using high priming doses of CTLA-4 inhibition and/or continuous dosing alone and in combination with PD-1 blockade influences the dynamics of the anti-tumour immune response.
3) How the above mechanisms may differ when PD-1 and CTLA-4 are inhibited using a monovalent bispecific targeting these two pathways.
Collectively, this research will interrogate precisely how combined targeting of CTLA-4 and PD-1 alter the response, and build evidence of how these pathways should be optimally targeted to ensure that more cancer patients benefit.
Apply using course: DPhil in Clinical Medicine
