Led by Gordon Cook (WS1: myeloma research lead, frailty, immune dysfunction and senescence) and Eve Roman (WS3 York: Epidemiology and Cancer Statistics Group Director, haematological cancers, study design cancer epidemiology), this theme comprises a multidisciplinary team of researchers working across three interlinked WSs.
WS1: Prof Gordon Cook; Immunosenescence and mature B-cell malignancies
Grand challenge: improve outcomes for patients with B-cell malignancies through delivering personalised medicine based on host response biology (HRB). HRB, the measurable pathophysiological processes resulting from the impact of disease and accelerated aging on biological function. It can be measured in immune function and infection/vaccination efficiency, inflammation, adipose/muscle metabolism (immunometabolic dysfunction) and cardiovascular risk. HRB may be used to define predisposition to frailty syndrome. This WS addresses questions including:
1. Is accelerated ageing of the immune system, including effector cells and microenvironment (immunosenescence), associated with mature B-cell malignancies?
2. Do mature B-cell malignancies induce/augment immunosenescence?
3. What is the biological basis of tumour induced/augmented immunosenescence?
4. Is tumour induced/augmented immunosenescence reversible?
5. How does immunosenescence of B-cell malignancies affect systemic functionality and risk of therapy intolerance, adverse effects and mortality?
WS2: Dr Darren Newton; Immunity, inflammation and clonal haematopoiesis
Grand challenge: define the mechanisms of clonal haematopoiesis and enhance treatments of complex multisystem disorders. Clonal haematopoiesis has emerged as an important manifestation in age-related genetic damage, with ill-defined links to frailty and immunological senescence. Our work contributes to defining its mechanisms and enhancing treatments of complex multisystem disorders. Understanding the role of inflammation and immune selection in clonal haematopoiesis is key to the development of specific immune modulators in treating disorders such as aplastic anaemia, MPNs (myeloproliferative neoplasms), PNH (paroxysmal nocturnal haemoglobinuria), VEXAS (Vacuoles/E1 enzyme/X-linked/Autoinflammatory/Somatic syndrome) and histiocytic conditions. The paradigm we established for the pathophysiology and treatment of the ultra-orphan disorder PNH by targeting the complement pathway, resulted in effective treatment that transformed outcomes for patients, and established the PNH national service and PNH Research Tissue Bank in Leeds. This led to advances in treatment of multiple complement-mediated disorders, and we are currently exploring alternative complement inhibitors across multiple clinical trials. Our ability to deliver step changes in the context of rare diseases sets the paradigm for how such mechanistic insights can lead to fundamental changes in patient pathways, outcomes, quality-of-life and service delivery. Rare syndromes like PNH, Schnitzler’s and VEXAS illustrate how clonal haematopoietic and immunological populations intersect with immune dysfunction, autoinflammation, frailty syndromes and HRB that are the focus of WS1 and primary determinants of patient outcome. Other haematological malignancies are not infrequently preceded by, or follow after, a diagnosis of clonal haematopoiesis or myelodysplasia. Yet the extent to which clonal haematopoietic processes drive the decline in system-wide function is poorly understood. This WS integrates our expertise in immunohaematology and cytokine biology, using single cell transcriptomics and molecular imaging to understand the interplay between haematological clonality and multisystem manifestations of these diseases. Our work will leverage the enhanced assessment of HRB and immunosenescence in WS1 and population-based epidemiology and data science of haematological neoplasia in WS3, to define and understand the intersect between clonal haematopoietic processes and multisystem manifestations of ageing, frailty and cancer.
Grand challenge: integrating real-world patient and molecular data, we will develop prognostic and predictive biomarkers to improve patient outcomes. With the aim of enhancing therapeutic stratification of B-cell malignancies at key points along the patient pathway, this WS addresses the deficit of granular clinical, diagnostic, and host factor details in real-world settings. Integrating NHS data with molecular and cellular information on host and disease within HMRN will enable the development of prognostic and predictive biomarkers for testing in clinical trials and real-world settings. Incorporating wider patient characteristics identified in WS1 and WS2, our focus is to: understand features of early-progressors and treatment non-responders, managed in accordance with current guidelines; track disease evolution across the patient pathway; defining critical points and optimal treatment choices; link disease biology with aging and frailty to define markers of tolerance and efficacy, and optimise care.
Infrastructural and methodological developments central to achieving these aims include:
1. Software engineering to provide access in appropriately governed computational environments (AI/Core), integrating data rom the NHS, HMRN, and clinical trials.
2. Creating/augmenting datasets, including incorporation of ‘omics and digitised pathology.
3. Integration of clinical and molecular pathology with body composition imaging, applying methods from statistics, causal inference, epidemiology, image analysis and AI.
4. Examining interactions between genome changes, gene expression, cell morphology, (immune) microenvironment, and tissue distribution.