NIHRDataInsights/HRCSData huggingface dataset:
Title: Development and evaluation of T- and innate-cell engagers driving agonistic activity independent of Fc/FcReceptor interactions
Funder: Cancer Research UK

Abstract: Background: Antibodies targeting the immune checkpoints CTLA-4 and PD-1 revolutionised the field of cancer immunotherapy. Following these successes, new biotherapeutics that synergise with checkpoint inhibitors (CPI) by directly activating immune cells (agonistic agents) demonstrated great promise in pre-clinical models. However, their limited clinical impact underscores the need for a better understanding of the mechanisms underpinning their function (or lack thereof) to inform the rational development of clinically effective immune agonistic agents. Funded by our previous CRUK-Biotherapeutics grant, we investigated the role of Fc/FcReceptor (FcR) interactions in the activity of CPIs and agonistic antibodies. We demonstrated that high antigen density and activating FcRs play a key role in promoting depletion of tumour infiltrating regulatory T-cells by both anti-CTLA-4 antibodies and a new anti-CD25 antibody developed by our team (which is currently under clinical evaluation). We also demonstrated that agonistic antibodies against both B7 family members (i.e. ICOS) and TNFRSF members (i.e. OX40) can benefit from FcR-binding and Treg-depleting activity, but that unexpected depletion of activated effector T-cells can significantly limit their in vivo anti-tumour activity. Together, our data supports the development of new agents able to deliver agonistic activity in absence of Fc/FcR interactions. Aims: We propose to establish a platform for production and evaluation of T- and innate-cell engagers engineered to drive agonistic activity independent of Fc/FcR interactions. We hypothesise that the absence of FcR engagement will prevent unwanted depletion of activated T cells through activating FcR-engagement, whilst also preventing engagement of the inhibitory FcRIIB. We believe this last component is critical as binding to FcRIIB has been associated to toxicity induced by agonistic antibodies as well as immune-suppression of myeloid and antigen-presenting cells. Methods: We will establish a toolbox of binding sequences and combine the variable regions of antibodies targeting tumour associated antigens with antibodies that engage either agonistic receptors on T-cells or activating FcR on innate cells. After validation of binding and agonistic activity in vitro we will evaluate their in vivo activity and mechanism of action in mouse models of cancer and their impact in the human tumour microenvironment in a new patient derived immune xenograft model. How the results of the research will be used: Our results will provide the foundation for the rational design of T- and innate-cell engagers driving Fc/FcR-independent agonistic activity, a platform for their evaluation and improvement, and potential candidate T- and innate-agonistic molecules for later clinical evaluation.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/17/019 HR-MB: An international High-Risk Medulloblastoma trial
Funder: Cancer Research UK

Abstract: Background. Medulloblastoma (MB) is the most common malignant brain tumour in children and young people of which around 30% are diagnosed with High Risk disease (5 year EFS of c.60%). High-risk MB (HRMB) is defined clinically by the presence of one or more of the following high-risk factors; metastatic disease, large cell/anaplastic histology, significant residual disease post-surgery, Patients that are cured have significant long term toxicity (including neurocognitive and endocrinological). There has been a worldwide paucity of large clinical trials for HRMB and current clinical practice is based on a number of small national or institutional trials that provide limited information on how to best treat these patients. In addition improved understanding of the biology of these tumours will enable improved risk stratification. Aims. To evaluate whether outcome in children, young people and adults with HRMB is improved, compared with with conventional (once a day) radiotherapy (RT), for those treated hyperfractionated accelerated RT (HART) or high-dose therapy (HDT) with thiotepa followed by conventional RT and whether outcome in HR-MB is different for those treated with two different maintenance chemotherapy therapies. In addition the late effects of the various treatment arms will be determined. Comprehensive prospective biological studies in high-risk medulloblastoma, with the aims of: i) understanding the biological basis of HR-MB; ii) identification and validation of diagnostic and prognostic biomarkers; iii) identification and validation of molecular targets with therapeutic potential, and associated predictive biomarkers will be undertaken. Methods. The proposed trial is a randomised controlled trial that will evaluate outcome using differing chemotherapy and RT strategies for patients diagnosed with HRMB. Eligible patients will be identified post surgery and following national centralised diagnostic molecular profiling to identify patients with high-risk disease. The trial will assess alternative treatment approaches that may improve survival without significantly increasing toxicity. Two ways in which this intensification can be achieved are to increase the dose of RT or to increase the chemotherapy by giving HDT with stem cell rescue. Three arms will be compared in a randomised fashion (R1) (with biological selection and balancing): (i) the current European standard treatment (as above) (ii) an arm based on HDT and (iii) an arm based on the use of HART and R2 will evaluate oral temozolomide versus standard intravenous maintenance chemotherapy. The results of this research will be used to guide future treatments for HRMB including using biological biomarkers discovered during this trail to further refine treatment.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/22/004: PROTIS: A phase III trial of proton beam therapy versus intensity-modulated radiotherapy for the treatment of sinonasal malignancy
Funder: Cancer Research UK

Abstract: PROTIS: PROton beam Therapy versus Intensity-modulated radiotherapy for Sinonasal cancer Background Sinonasal malignancy is a rare, aggressive disease that usually presents at a locally advanced stage. The standard treatment is surgical resection with adjuvant (chemo-)intensity-modulated radiotherapy (IMRT). The 5-year disease free survival (DFS) and overall survival (OS) rates are approximately 40% and 50% respectively. About 20% of patients develop severe late radiation toxicities and impaired quality of life. Observational data and a systematic review from a number of non-comparative studies suggest use of proton beam therapy (PBT) compared with IMRT improves disease control and survival outcomes with a favourable toxicity profile. Aims For locoregionally advanced, non-metastatic sinonasal carcinoma: (1) Assess whether PBT improves disease-free survival time compared with IMRT; (2) establish the disease control, survival, toxicity and quality of life benefits for PBT; (3) standardise and quality assure radiotherapy for a difficult to treat cancer; (4) optimise MDT decision making between UK centres for a rare cancer; (5) embed genomics, radiobiology, physics and immunology research to address the most pressing translational questions for sinonasal cancer and PBT. Methods 276 patients with locally advanced sinonasal cancer from 20 UK centres will be recruited over five years and randomised to PBT versus IMRT. (Chemo)-radiotherapy will mainly be used in the post-operative setting (~80% of patients), with primary (chemo-)radiotherapy for inoperable disease, or following response to induction chemotherapy for sinonasal undifferentiated carcinomas. Disease control will be assessed clinically and by standard imaging. Physician recorded CTCAE v5.0 toxicities, health related quality of life (EORTC-QLQ-C30, EORTC-QLQ-BN20, EuroQoL EQ-5D-5L) and objective measures of late toxicities will be performed for visual-orbital, neurocognitive, trismus, hearing, olfactory and pituitary/hormonal dysfunction. Quality assurance of radiotherapy volume delineation and planning will be performed by the NCRI funded Radiotherapy Clinical Trials Quality Assurance group. National virtual MDT working will be introduced to standardise the treatment approach for a rare cancer. Blood and tissue samples, radiotherapy treatment plans and surveillance MRI scans shall be collected for translational research. How the results of this research will be used PROTIS will have national and international impact by defining the standard of care for sinonasal cancer. Should the trial meets its objectives, PBT will be routinely commissioned by the NHS for the treatment of sinonasal cancer. State of the art translational science will inform, refine and personalise the treatments for sinonasal cancers and use of PBT.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Utilising Cancer Genetic Evolution for Early Detection and Monitoring of Breast Cancer
Funder: Cancer Research UK

Abstract: Intra-tumoural sub-clonal heterogeneity is known to limit a patient’s overall response to both targeted treatments and more generalised therapy in metastatic breast cancer. Landmark studies in patients with metastatic breast cancer have illustrated the potential of circulating tumour DNA (ctDNA) as a “liquid biopsy” for monitoring patients on treatment and for selecting targeted therapies. However, the impact of ctDNA screening in metastatic disease will ultimately be limited due to the ability of multiple metastatic clones to evolve and resist targeted therapies. The purpose of this programme is to determine the optimum circulating biomarkers for detection of breast cancer in patients with early-stage disease, for monitoring the disease free interval and early detection of resistance to endocrine therapy, which is the major cause of breast cancer death. We are exploring markers in cfDNA and circulating tumour cells (CTCs) and will compare these with tumour biopsy to determine the degree to which they are representative of tumour burden. In early screen detected breast cancer we correlate tumour sequencing data with blood markers and determine the “normal” blood profile of healthy age matched controls. We will determine the optimum circulating markers for prediction of resistance and relapse, through comparison of blood and tissue by molecular profiling of mutations and copy number variation in key cancer genes that may drive breast cancer progression. We will also explore tumour educated platelets (TEPs), as novel blood biomarkers of breast cancer, and nucleosome footprints as a novel approach to monitoring oestrogen receptor (ERa) activity in cfDNA. The use of cfDNA as a biomarker to monitor transcriptional to improve personalized medicine is yet to be explored. The potential significance is that blood testing could aid with stratification and targeting therapy at an early stage and may offer a window of opportunity when there is less potential for development of drug resistance, than that encountered in the treatment of advanced cancers.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Harnessing the lymphoid tissue niche to boost anti-tumour immunity
Funder: Cancer Research UK

Abstract: Background Anti-tumour immune responses can eliminate cancer cells in primary or metastatic sites and provide long-lasting protection against relapse. But cancer cells have developed a plethora of mechanisms to evade immune detection and to suppress immune function meaning that immune responses commonly fail to control tumour growth. The development of immunotherapies in the form of cytokines, monoclonal antibodies, cancer vaccines and genetically-engineered T cells work to counteract immunosuppression in tumours and has revolutionised cancer treatment. But immunotherapy approaches do not work for all patients and we have not yet harnessed their full potential. Adaptive immune responses, including anti-tumour immune responses, require the support of lymphoid tissues. We propose to harness the lymphoid tissue niche – in lymph nodes (OB1), within tumours (OB2) and synthetically engineered scaffolds (OB3) – to increase numbers of effector T cells, help overcome T cell exhaustion, and support immunological memory. Aims: We will investigate the importance of the tumour-draining lymph node in systemic anti-tumour immunity and investigate how cancer cells cause lymph node dysfunction. In the tumour microenvironment we will investigate cues promoting differentiation of ‘immunofibroblasts’ and tertiary lymphoid structure formation. In an alternative, interdisciplinary approach, we will use engineering approaches to test the potential of a bioengineered lymphoid tissue scaffold to improve responses to immunotherapy and patient outcomes. Methods: Using combination of microscopy, flow cytometry and single cell sequencing using genetically modified mouse models we will investigate the molecular determinants of the ‘immunofibroblast phenotype’. We will use a new conditional fibroblast targeting model generated by our lab to test specific hypotheses and gain mechanistic understanding. We will investigate microenvironment cues promoting differentiation of lymphoid fibroblasts and development of ectopic lymphoid tissue in tumours using CITE-seq. We will extend this work to understand stromal responses to radiotherapy treatment and the impact of reactive fibroblasts on immune cell infiltration. Finally, we will construct lymphoid tissue-inspired synthetic scaffolds based on the topology of lymphoid tissues in vivo and determine if bioengineered scaffolds can support lymphocyte survival, proliferation and differentiation and impact tumour progression when implanted into mouse models. How the results of this research will be used: If we achieve our objectives, more patients would respond to immunotherapy and achieve long term remission. These projects will reveal functionally relevant and druggable targets to reprogramme cancer-associated fibroblasts in the tumour microenvironment to bolster anti-tumour immunity, offering an adjunct to existing immunotherapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Tracing the dynamics of epithelial cell competition in normal and perturbed states
Funder: Wellcome Trust

Abstract: The mechanisms that regulate cell fate promise fundamental insights into the pathways that promote tumour growth. Through advances in genetic lineage tracing and single-cell profiling, the functional identity, lineage relationships and fate behaviour of stem and progenitor cells have begun to resolve. Applied to epithelial tissues, these studies have challenged prevailing models, emphasizing the role of stochastic renewal programmes, fate priming and the flexibility of cell states during regeneration. Using a novel lineage tracing strategy based on variants of the multicolour Confetti reporter system, we will use quantitative modelling-based approaches to target the cellular and molecular mechanisms of epithelial cell fate, and how these programmes become subverted following the activation of oncogenic mutations. With a focus on columnar and squamous epithelia, where a foundational understanding of associated signalling pathways and transcriptional programmes is in place, we will define at clonal resolution the changes that take place in cell fate following the acquisition of oncogenic mutations, targeting tumour cells and the reaction of surrounding normal tissue – the tumour microenvironment. As prominent sites of disease, we will contrast tumour cell dynamics in the closed glandular arrangement of the intestinal epithelium and the open organization of the interfollicular skin epidermis and oesophagus.

Lay abstract: Epithelia comprise a variety of specialised differentiated cell types that ensure a diversity of functions. To ensure their maintenance, epithelia constantly renew, replacing cells lost through exhaustion or damage. This process is undertaken by stem cells – specialised tissue-specific cells – that renew through division, while giving rise to differentiating progeny. A key challenge in epithelial biology is to understand how stem cells maintain the balance between proliferation and differentiation, and how these programmes become corrupted during tumour development. To target these questions, we will use of a new transgenic mouse model in which the random induction of fluorescent reporter genes allows the fate of individual cells to be tracked. By coupling the red reporter with the activation of cancer genes, we will use quantitative modelling to define the changes that take place in cell fate following the acquisition of mutations, targeting tumour cells and the reaction of surrounding tissue.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Novel microstructural (VERDICT and T2 mapping) and metabolic (hyperpolarised 13C-Pyruvate) MR in diagnosis, risk-stratification and treatment response assessment of prostate cancer
Funder: Cancer Research UK

Abstract: Background: For the last 50 years we have been applying Prostate Specific Antigen (PSA)-Biopsy risk-stratification to men at risk of prostate cancer and we now know that it is not fit for purpose. It results in the greatest burden in all oncology of over-diagnosis, over-treatment, and of missed cancers that are of clinical importance. This systematic error has biased our tissue archives, skewed our risk calculators, rendered our trials un-representative and undermined policy-making. We and others have shown that multi-parametric MRI (mp-MRI) provides a solution to the errors associated with the traditional PSA-Biopsy approach and identifies a distinct stratum of men, from the wider population at risk, that is closely correlated to the two strongest known predictors of disease aggressiveness - grade and volume. But, there remain significant diagnostic and prognostic challenges with applying an mp-MRI and targeted biopsy approach to manage patients with prostate cancer. Aims: We aim to: (i) improve the diagnostic performance of mp-MRI by development and integration of novel MrI methods capable if detailed assessment of microstructure and metabolism; (ii) identify the imaging endotype in patients with early prostate cancer that is assocaited with aggressive disease to avoid overtreatment of patients. Methods: We propose a translational imaging programme that closely follows the CRUK imaging biomarker roadmap and works through technical validation at single and multiple site; biological validation of MR signals to understand their origins, and culminates in clinical evaluation studies addressing the diagnostic and prognostic challenges in patients. How the results of the research will be used: The study would directly impact on the care of patients, helping patients avoid unnecessary biopsy when there is no cancer and mp-MRI is positive, avoiding significant cancer being missed when mp-MRI is negative, avoiding patients having indeterminate mp-MRI scans that do not add value to management. Moreover, if we can use these techniques to identify an phenotype of cancer that is more aggressive we can avoid patients with indolent disease receiving unnecessary treatment and the consequences of associated side effects. The study will also enable application of developed techniques in other cancers as the technologies developed would be generic enough to be applied to alternative cancer challenges.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Global surveillance of cancer survival (CONCORD-4): 20-year trends in survival from 22 adult cancers and all childhood cancers, for patients diagnosed during 2000-2019 or later
Funder: Cancer Research UK

Abstract: Background Cancer is a greater public health challenge than COVID-19, which caused more than 5 million deaths during 2020-21. It is estimated that almost 10 million people died of cancer in 2020 alone. Projections suggest that over 22 million people will be diagnosed in 2030, a 24% increase, and almost 13 million deaths, an increase of 30%. Unlike COVID-19, cancer is a heterogeneous set of many diseases; the public health problem will also be much longer-term. Rational assessment of global progress in cancer control requires reliable information on trends in survival. These trends reflect the extent to which cancer patients world-wide have access to prompt diagnosis, optimal treatment and the best possible outcome, including cure. Aims CONCORD aims to provide long-term and up-to-date surveillance of world-wide trends and inequalities in survival, to inform strategies for cancer control. Methods CONCORD-4 will include data for all cancers in children, and for patients diagnosed with one of 22 cancers that represent 84-90% of all adult cancers. We will examine trends in net survival, and in statistical “cure” and avoidable premature deaths, among patients diagnosed during the 20 years 2000-2019, and for more recent years where data are available, by age and for all ages combined. We expect to analyse individual records for 50 million patients, provided by up to 400 registries covering a combined population of more than 1 billion people, in up to 80 countries world-wide. We will use the Pohar Perme estimator to estimate net survival at 1, 5 and 10 years. We will construct life tables of all-cause mortality by single year of age, sex, ethnicity and calendar year, for each country or region, to control for competing risks of death. How the results of this research will be used CONCORD-4 will provide up-to-date, real-world evidence on whether population-based cancer survival is improving in the UK, but also for international comparisons. The results will reflect the overall effectiveness of health services in managing all cancer patients, not just the small proportion recruited to trials. The results will be used to inform national and global policies for cancer control, by national health ministries; by OECD; by WHO’s Global Initiative for Childhood Cancer and its Global Breast Cancer Initiative, and by the EU Cancer Mission. CONCORD-4 survival estimates will also provide a baseline against which to evaluate the impact on cancer outcomes of the COVID-19 pandemic, which has disrupted cancer services world-wide.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS