NIHRDataInsights/HRCSData huggingface dataset:
Title: Deep Learning for CAR-T cell therapy optimisation
Funder: Medical Research Council

Abstract: Adoptive cell therapy is a treatment of patients using their own, modified immune cells. It involves harvesting T cells - the immune cells that normally recognise and eliminate pathogens - from the patients blood, reprogramming them to recognise cancer cells and re-introducing the newly modified cells back into the patient to destroy tumours. The modifying factor used to arm these T cells against cancer is called Chimeric Antigen Receptor or CAR, in short. Using the lock and key analogy, just as every lock can only be opened with the appropriate key, each type of cancer, with its unique antigens, can only be recognised by a specific engineered CAR. The concerted efforts into development of specific CAR therapies against other cancers are hindered by the tedious process of target discovery and receptor optimisation. Coding.bio streamlined the process of building better receptors, making it faster, cheaper, and more diverse. This project will develop deep learning methods to select lead candidates from big datasets of these receptors, making candidates more likely to succeed in the clinic The coding.bio platform will generate large datasets with thousands of variations of engineered CAR molecules and an associated readout score of how effective it is as a therapeutic. This data will be ideal for fine-tuning a deep learning methods. We will initially focus our efforts on transformer based bio-embedding methods coming from the field of Natural language processing such as Prot-BERT which have recently been pre-trained on hundreds of millions of protein sequences. These methods have demonstrated state of the art performance when fine-tuned for a number of classic protein bioinformatic prediction challenges. We will also explore existing established ML methods, but will also track new innovations in the fast moving field of bio-embeddings such as those emerging from embedding of multiple sequence alignments of proteins.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Multi-scale mechanochemical signals regulating cancer cell survival and invasive potential
Funder: Medical Research Council

Abstract: Our Programme will address an important emerging concept in cancer biology concerning the impact of tumour biomechanics on head & neck cancer cell adaptation and response to therapy. Our own data, and that of other groups suggest mechanical forces in the tumour microenvironment can enable tumour cell adaptation through changes in levels and localisation of cytoskeletal-associated proteins. This leads to altered nuclear envelope integrity, DNA damage response, exosome secretion and immune cell function. However, the key cytoskeletal-associated proteins involved in these responses remain unknown, and we hypothesise that identifying these proteins and analysing their function in vitro and patient samples will lead to new biomarkers and targets for therapeutic intervention. We will adopt a multi-disciplinary approach to analyse human head and neck cancer cell responses to mechanical changes using longitudinal imaging of 3D culture models with tuned stiffness that reflect those seen in patients. Within these models we will firstly explore changes to the subcellular distribution of the proteome in response to increasing stiffness, using unbiased multi-plexed proteomics and functional imaging to analyse cell viability, invasion and DNA damage. We will determine how target proteins already identified by us impact on these events, and how biomechanics alter exosome secretion. We will further define how these changes affect cancer cell resistance to chemotherapy, tumour-immune cell interactions using 3D co-culture models and functional imaging. Finally, we will align our discoveries with an ongoing clinical trial to understand whether changes to our novel mechano-responsive targets correlate with patient tumour mechanics and the functional importance of these in patient-derived organoids. Data arising from our study will greatly enhance our understanding of tumour cell responses to biomechanical changes and identify new biomarkers and targets for therapeutic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Crosstalk Between Tumour and Draining Lymph Nodes and its Impact on Triple-Negative Breast Cancer
Funder: Medical Research Council

Abstract: The presence and extent of lymph node (LN) metastasis is associated with shorter disease-free and overall survival in triple negative breast cancer, but LNs, as well as being typically the first site of seeding of many solid tumours, also serve as immunological hubs between the tumour and the patient's systemic immunity. Work from our team showed for the first time that in triple negative breast cancer patients with low tumour infiltrating lymphocytes (TILs), time to progression of disease was prolonged when their LNs displayed formation of germinal centers. Germinal centers represent locations within LNs where different B cell populations are produced for effective adaptive immune responses. These findings underscore our hypothesis that these patients display activation of the immune system at their LNs and these play a critical role in the immune response to the tumour. Thus, our research raises awareness of the biological and translational value to assess LNs above and beyond the presence and size of cancer cells deposits, next to the assessment of tumour infiltrating lymphocytes. Here, we propose to use a combination of approaches, including spatial transcriptomics, single cell RNA-seq, BCR-seq, imaging and mouse models to: 1) dissect the cellular, molecular and spatial organisation similarities between tumour draining (td)-LNs, TILs and TLSs; 2) characterise td-LNs GCs properties, function and impact in the context of therapy; 3) Determine the signals mediating the crosstalk between the tumour and td-LNs. Our work will provide the first insights into the functional role of distinct B cells at the tumour and in LNs, potentially uncovering targets to develop therapeutic strategies for high-risk triple negative breast cancer patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Engineering synthetic adhesion receptors to enhance the sensitivity of therapeutic chimeric antigen receptors
Funder: Medical Research Council

Abstract: T cells patrol the body in search of antigens derived from infectious organisms or cancer cells. They use their T cell antigen receptors (TCRs) to recognise peptide antigens on major-histocompatibility-complexes (pMHC). T cells have remarkable antigen sensitivity; they can become activated when recognising only a single pMHC. This high sensitivity is important because infectious organisms and cancers deploy evasion mechanisms to reduce the amount of antigen presented to T cells. T cells are now engineered to recognise cancer antigens using chimeric antigen receptors (CARs). This therapy is approved to treat B cell cancers. However, many patients relapse with B cells that express low levels of the target antigen. It is now clear that CARs have a profound defect in antigen sensitivity; CARs require 100-1000-fold more antigen than the TCR to activate T cells. There is an urgent need to increase the sensitivity of CARs to prevent these relapses The high antigen sensitivity of the TCR is partly a result of their adhesion receptor CD2 binding to its ligand CD58. The CD2/CD58 and TCR/pMHC complexes share a similar intermembrane distance of 14 nm. Therefore, many CD2/CD58 complexes are able to precisely align membranes to allow TCRs to efficiently bind the low numbers of pMHCs. Here, we hypothesise that CARs, which are larger than TCRs and target antigens that vary in size, will have different membrane alignment requirements that are not optimised by native CD2/CD58. Using an interdisciplinary approach that combines quantitative and synthetic biology and immunology, we will design novel adhesion receptors that optimise membrane alignment for existing and novel CARs to endow them with the same high antigen sensitivity as the TCR. This will improve existing CAR-T cell treatments for B cell cancers and should allow for new treatments to eliminate cancers expressing low levels of target antigens.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Translational development of novel immunotherapeutic targets in Oesophageal Cancer
Funder: Medical Research Council

Abstract: The UK has both the highest global incidence of oesophageal adenocarcinoma (OAC) and a poor 5-year survival rate with only 40% of patients able to undergo potentially curative treatment. At the current time there is limited information in this regard, particularly regarding the T cell immune responses to OAC which is the focus of this application. I hypothesize that T cells within the OAC tumour microenvironment can initially generate a tumour-specific response but that these become functionally suppressed during tumour progression. Immunotherapies such as PD-1-targeted 'checkpoint blockade' are likely to hold future promise in therapy but their application is limited by knowledge of the OAC-specific T cell response. The proposed study will build on 3 years of research collaboration between Professor Moss and Mr Griffiths focussing on the immune contexture and transcriptomic landscape of OAC. This has shown that OAC tumours contain a heterogeneous population of antigen-experienced T cells with a predominant 'tissue resident memory' phenotype. Experience from other tumours suggests that these are likely to include tumour-specific cells but their specificity and functional activity remain unclear. Here I will build on these emerging studies to: -determine the relation between phenotype and functional activity of T cells within the OAC microenvironment -assess the architecture of T cell infiltration within tumour and its relation to chemotherapy response and survival through use of 7-parameter multiplexed IHC -use in vitro assays and organoid systems to develop novel immunotherapy approaches for patients with OAC. My aim is to delineate how regulatory interactions between tumour and immune cells within OAC might be disrupted in order to to identify novel targets for immunotherapy which has the potential to transform clinical outcomes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: The clinical and cost effectiveness of lung cancer screening by low dose CT
Funder: Department of Health and Social Care

Abstract: • Lung cancer is a serious condition with a poor outlook, causing death before 1 year after diagnosis in the majority of cases._x000D_ • It is primarily caused by smoking._x000D_ • Although smoking rates are falling, the number of cases of lung cancer will remain substantial for many years because smoking is still common, it takes several years for lung cancer risk to fall after someone has stopped smoking and because there are other causes of cancer e.g. exposure to asbestos. Smoking rates are still rising in developing countries_x000D_ • Lung cancer can be successfully treated by surgery if it is identified early_x000D_ • Unfortunately for most people symptoms alerting to the possibility of lung cancer do not occur until the lung cancer is relatively large, and usually too advanced to be removed by surgery_x000D_ • Using medical imaging to identify lung cancers when they are small before a person has any symptoms (“screening”) is thus a logical approach which has been the subject of several trials over the last 30 years_x000D_ • Traditional chest x-rays have been previously used to screen for lung cancer but were not found to reduce the number of deaths from lung cancer_x000D_ • However new ways of imaging the lungs such as low dose CT-scanning (computed tomography), which allow the lungs to be seen in 3D, have shown more encouraging results_x000D_ • There are other tests, at an earlier stage of development, which might be used to screen for lung cancer, but these are not considered in this report_x000D_ • This piece of research will systematically review the evidence on the effectiveness and cost-effectiveness of screening for lung cancer with low dose CT scanning. _x000D_ • This will be done by an independent academic group.

Lay abstract: The research proposed is in response to a brief which requests:_x000D_ “Could lung cancer screening by low dose CT be cost effective in the UK?”

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Lenvatinib plus pembrolizumab for untreated advanced renal cell carcinoma [ID3760]
Funder: Department of Health and Social Care

Abstract: Renal cell carcinoma is a cancer affecting the lining of small tubes in the kidneys. This type of cancer often forms without patients having any symptoms and around 50% of all patients have cancer that has spread beyond the kidneys. This group of patients can be treated with either a single drug or, in some cases, two drugs given together. We will review how well a new combination of drugs (lenvatinib plus pembrolizumab) works. We will also explore the value for money of this new treatment combination compared with other treatments used to treat NHS patients.

Lay abstract: The remit of this review is to appraise the clinical and cost effectiveness of lenvatinib in combination with pembrolizumab (lenvatinib+pembrolizumab) within its European Medicines Agency (EMA) marketing authorisation for the treatment of untreated advanced renal cell carcinoma (RCC).

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Atezolizumab for adjuvant treatment of resected non-small-cell lung cancer [ID3852]
Funder: Department of Health and Social Care

Abstract: Lung cancer is the third most common cancer and the most common cause of cancer death in the UK, accounting for 13% of all new cancer cases and 21% of all cancer deaths in 2017. [1] There are around 38,900 new lung cancer cases and 27,700 deaths from lung cancer in the England every year. Up to 85% of lung cancers are nonsmall-cell lung cancers (NSCLC). [2]_x000D_ _x000D_ Most lung cancers are diagnosed at an advanced stage, when the cancer has spread to lymph nodes and other organs in the chest (locally advanced disease; stage III) or to other parts of the body (metastatic disease; stage IV). Less than 30% of lung cancers are diagnosed at an early stage (stage I or II)._x000D_ _x000D_ NICE guideline Lung cancer: diagnosis and management recommends surgery, radiotherapy, chemoradiotherapy or a combination of these for early stage disease.[3] Around 18% of people with NSCLC had surgical resection with curative intent in England and Wales in 2017. [4] If well enough, people may be offered a cisplatin-based chemotherapy (adjuvant treatment) after surgery. [3] People are actively monitored for cancer recurrence. If the cancer comes back, treatment options and prognosis depend on the site of the recurrence. Despite the curative intent of treatment for early-stage lung cancer, survival is poor, with only about 57% people with stage I, 34% with stage II and 13% with stage III surviving for 5 years after diagnosis. [1]_x000D_ _x000D_ It is estimated that over half of all NSCLCs express the programmed cell death ligand-1 (PD-L1) biomarker. [5] Cancer cells expressing PD-L1 are believed to suppress certain immune responses and cause increased tumor aggressiveness._x000D_ _x000D_ References_x000D_ _x000D_ 1. Lung cancer statistics. Cancer Research UK. Accessed August 2021_x000D_ _x000D_ 2. Types of lung cancer. Cancer Research UK. Accessed August 2021_x000D_ _x000D_ 3. Lung cancer: diagnosis and management. (2019) NICE guideline 122_x000D_ _x000D_ 4. National Lung Cancer Audit: Annual report 2018 (for the audit period 2017)(2020). Royal College of Physicians. Accessed August 2021._x000D_ _x000D_ 5. Skov, B., Rørvig, S., Jensen, T. et al. (2020) The prevalence of programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer in an unselected, consecutive population. Mod Pathol 33, 109–117

Lay abstract: To appraise the clinical and cost effectiveness of atezolizumab within its marketing authorisation for adjuvant treatment of resected non-small-cell lung cancer.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Ruxolitinib for treating polycythaemia vera (ID5106)
Funder: Department of Health and Social Care

Abstract: Polycythaemia vera is a bone marrow disease that leads to an increase in the number of blood cells (primarily red blood cells). As more red blood cells are made, the blood becomes thicker which can lead to complications such as gout, bleeding problems and blood clots. Blood clots can cause strokes, heart attacks, or blockage of an artery in your lungs (pulmonary embolism) or in a vein deep within a muscle (deep vein thrombosis). Polycythaemia vera can also cause an increase in white blood cells which can lead to severe itching. In some cases, the extra cells collect in the spleen which may then become enlarged (splenomegaly). Polycythaemia vera can lead to other problems such as scarring of the bone marrow (myelofibrosis) and acute myeloid leukaemia. _x000D_ _x000D_ Polycythaemia vera can affect people of any age, but is most prevalent in people aged over 60, and in men[1] . The UK prevalence based on the population enrolled in The Health Improvement Network is approximately 6.8 per 100,000. Approximately 5% to 15% of people with polycythaemia vera go on to have myelofibrosis[2] . _x000D_ _x000D_ Current treatments for polycythaemia vera aim to prevent symptoms and complications, and to minimise the risk of transformation to acute myeloid leukaemia or myelofibrosis, therefore improving survival. The British Committee for Standards in Haematology’s guidelines for polycythaemia vera recommend a range of treatments including periodic phlebotomy (bloodletting), hydroxycarbamide (also referred to as hydroxyurea), interferon, anagrelide, radioactive phosphorus or low dose busulphan. In addition, melphalan has a license for treating polycythaemia vera in the UK but is rarely used in clinical practice. NICE was previously unable to make a recommendation for ruxolitinib for treating polycythaemia vera because no evidence submission was received for the technology (TA356)._x000D_ _x000D_ References_x000D_ 1. Macmillan (2019) Polycythaemia vera [accessed 1 June 2022_x000D_ 2. NICE (2015) Ruxolitinib for treating polycythaemia vera that is resistant or intolerant to hydroxycarbamide: Final scope [accessed 30 June 2022]

Lay abstract: To evaluate the clinical and cost effectiveness of ruxolitinib within its marketing authorisation for treating polycythaemia vera that is resistant or intolerant to hydroxycarbamide.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Ibrutinib with venetoclax for untreated chronic lymphocytic leukaemia or small lymphocytic lymphoma [ID3860]
Funder: Department of Health and Social Care

Abstract: Chronic lymphocytic leukaemia (CLL) is the most common type of chronic leukaemia and is a type of cancer that affects the white blood cells. It tends to progress slowly over many years. CLL mostly affects people 60 years of age and over and is rare in people 40 years of age and younger. In England there were 3,157 new cases of CLL in 2017. The risk of developing CLL increases with age and is more common in men. 1_x000D_ _x000D_ In CLL, the material found inside some bones (bone marrow) produces too many white blood cells called lymphocytes that aren't fully developed and don't work properly. Over time this can cause a range of problems, such as an increased risk of picking up infections, persistent tiredness, swollen glands in the neck, armpits or groin, and unusual bleeding or bruising.2 People with CLL may live with a considerable burden of symptoms impacting on their quality of life, whether or not they have received treatment. Approximately 5% to 10% of people diagnosed with CLL are considered to have ‘high-risk’ disease, characterised by the presence of cytogenetic mutations or abnormalities (that is, a 17p deletion or TP53 mutation).3 The presence of a 17p deletion or TP53 mutation can increase both the rate of cell growth and the resistance of the disease to treatment. The presence of an unmutated immunoglobulin heavy chain gene (IgHV) may also lead to poorer clinical outcomes. _x000D_ _x000D_ Treatment options for untreated CLL depend on factors such as stage of disease, performance status and co-morbidities. Most people will not have symptoms when they first receive a diagnosis and will not need any treatment, if they don’t have any symptoms. Table 1 below summarises the treatment options which are currently available as routine practice in the NHS in England for untreated CLL._x000D_ _x000D_ _x000D_ _x000D_ 1. Cancer registration statistics, England: 2017 (2019). Office for National Statistics. Accessed July 2021._x000D_ 2. Chronic lymphocytic leukaemia. NHS Choices. accessed July 2021 _x000D_ 3. Eichhorst B, Robak T, Montserrat E et al. on behalf of the European Society for Medical Oncology (ESMO) Guidelines Committee (2015). Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and_x000D_ follow-up. Annals of Oncology 26 (S5): v78-v84.

Lay abstract: To appraise the clinical and cost effectiveness of ibrutinib with venetoclax within its marketing authorisation for untreated chronic lymphocytic leukaemia.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS