Melanoma is the deadliest form of skin cancer. Once melanoma has spread throughout the body, it is known as metastatic melanoma. At this stage melanoma becomes very difficult to treat and the standard treatment is effective only in a very small proportion of patients. In recent years new drugs have been approved for the treatment of metastatic melanoma. These drugs inhibit the molecules called PD-1 and CTLA-4 that are present on a subpopulation of white blood cells called T lymphocytes. Inhibition of PD-1 and CTLA-4 helps the immune system to attack the cancer. Although these drugs significantly extend lives of melanoma patients, complete responses upon combined inhibition of PD-1 and CTLA-4 are seen only in 11.5 % of the patients. It is therefore important to gain a better understanding of how these drugs work in order to be able to develop approaches that further improve their efficacy. Notably, the immune system works in different ways within different organs in the body. It is therefore important to understand how the drugs targeting PD-1 and CTLA-4 work within the organs to which melanoma most commonly spreads. Our goal is to understand how the efficacy of PD-1 and CTLA-4 blockade could be improved in the brain, to which cancer spreads in up to 60% of metastatic melanoma patients. The resulting tumours are called brain metastases (BrM) and they are particularly difficult to treat. In comparison to the melanoma in general, we know very little about BrM; this is because - despite their high incidence - patients with BrM are mostly excluded from clinical trials and BrM are experimentally strongly understudied. Notably, brain has a very distinct cellular composition and the presence of the blood-brain barrier restricts access of drugs and immune cells into the tumour. Ignoring these specifics of the brain poses a danger that - despite a progress in the treatment of melanoma in other parts of the body - treatment of BrM once again lacks behind and BrM become a limiting factor in patient survival. It is therefore critical to identify the mechanisms involved in the action of drugs targeting PD-1 and CTLA-4 in BrM in a timely manner. There are to date no experimental studies investigating how the drugs targeting PD-1 and CTLA-4 work in BrM. To study the latter, we established an in vivo model of melanoma BrM and demonstrated that a combined targeting of CTLA-4 and PD-1 significantly inhibits growth of BrM and prolongs the survival. This was mainly mediated by a subpopulation of T lymphocytes called Cytotoxic T lymphocytes (CTLs) and by another type of white blood cells called natural killer cells. CTLs accumulated in tumours following therapy. Therefore our goal is to understand how CTLs travel to BrM and to determine how they kill cancer cells in the context of this therapy. We also observed increased accumulation of white blood cells of so-called myeloid lineage in tumours. We therefore aim to determine whether these cells are also required for activity of drugs targeting PD-1 and CTLA-4 in the brain. Understanding how CTLs travel to BrM will enable the development of strategies that can enhance CTL accumulation within the tumour in the brain and are therefore expected to potentiate the efficacy of therapy targeting PD-1 and CTLA-4. If our study determines that white blood cells of myeloid lineage are involved in inhibition of BrM following targeting of PD-1 and CTLA-4, this will provide a rational for improved therapies combining targeting of PD-1/CTLA-4 and myeloid cells. At least part of the newly gained knowledge is expected to be applicable to melanoma at sites other than the brain. Thus, the knowledge emerging from the proposed research has a potential to contribute towards improved outcomes of patients with BrM and those with metastatic melanoma in general.

Valvular heart disease (VHD) has become an epidemic and nearly two million people in the UK suffer from it. This number is expected to double by 2040. About half of those affected by VHD are unaware of their condition. Early diagnosis is the key to providing essential treatment and preventing untimely death. We are developing an intelligent stethoscope to automatically detect heart murmurs and the underlying pathology, which would help provide early diagnosis of VHD. Currently, heart murmurs are picked up as a part of a physical exam by GP using a stethoscope. However, VHD can often become severe before symptoms develop, meaning many patients may only be picked up when they have already developed irreversible complications, such as heart failure, or post-mortem. The AI-enabled stethoscope proposed could provide a much higher accuracy than could be achieved by trained practitioners via auscultation. It could also be used by less-skilled healthcare professionals in a screening program for those at risk or by patients for at-home monitoring. This would reduce the number of missed diagnoses, reduce the burden on GPs of detection, and support early intervention to minimise morbidity and mortality.

Motor neurone disease (MND) is diagnosed in 1,200 people in the UK every year. It causes progressive paralysis and death on average within three years of symptom onset and there is currently only one licensed drug (riluzole) with only modest survival benefit. Drug trials in MND are time-consuming for patients and expensive for funders. A biomarker of disease activity is urgently needed to accelerate the pace of drug discovery. MND is caused by the progressive dysfunction and death of motor neurons. Ailing motor neurons in the spinal cord are electrically unstable and spontaneously discharge electrical impulses that cause small groups of muscle fibres to twitch (known as fasciculations). When the motor neuron becomes electrically unresponsive these fasciculations stop and the motor neuron subsequently dies. There is also some experimental evidence that the fasciculations may cause chemical disturbances that hasten the death of motor neurons. These muscle fasciculations can be seen under the skin and are one of the hallmark clinical signs of MND. Thus, recording the site and frequency of fasciculations over time may provide a good measure of motor neuron health. Conventional electrical testing (needle electromyography, NEMG) involves putting a fine needle deep into muscles to record fasciculations and this can only be done in a hospital. NEMG only detects electrical activity within a minute field, records data for only a few minutes and is quite painful so few patients would tolerate repeated testing. High-density surface EMG (HDSEMG), using a non-invasive sensor that sticks to the skin, can record fasciculations over a field that is 100 times larger than the needle. The test is painless so fasciculations can be recorded over many hours and repeated frequently. Under the guidance of Professors Chris Shaw and Kerry Mills, eminent in their respective fields of motor neurone disease and neurophysiology, I, as a clinician and neurology trainee, am currently undertaking a six-month preparatory feasibility study at King's College London. In this study, we are making use of commercially available HDSEMG sensors to record fasciculations at rest in patients with MND. We have recruited eight patients and are taking representative recordings from all four limbs simultaneously. The purpose of this study is to ensure this method is comfortable and convenient for patients, and that these preliminary data can be interpreted in the way we expect. We predict that the site, frequency and shape of fasciculations might provide a more sensitive measure of disease progression in an individual. Once calibrated, this method may then be used to assess the positive impact of a new drug if it reduces the regional spread and frequency of fasciculations. In order to calibrate this technique, we will conduct a 12-month longitudinal study, recruiting 24 patients from the King's College Hospital Motor Nerve Clinic, comprising a mixture of patients with MND and those with benign fasciculation syndrome. Patients in this latter group have fasciculations but do not develop weakness and have normal lifespans. They are therefore an optimal control group. At each visit, we will take resting HDSEMG recordings from all four limbs and perform standard clinical measures of disease progression. In addition to survival, these are the standard tests we use to see whether a drug is working in clinical trials. Ultimately, through collaboration with Bioengineering colleagues at Imperial College London, we hope to design a wearable ergonomic garment with embedded HDSEMG and remote data transfer capabilities. We envisage testing and calibrating this new equipment against our validated, well-established system. The portability of such a powerful tool will allow the assessment of patients in their own homes, potentially increasing the intensity of objective monitoring. This will prove an invaluable addition to future clinical drug trials.

Stem cell transplantation is the only curative therapy for many patients with acute myeloid leukaemia (AML) and other cancers of the blood and bone marrow. However, cancer recurrence remains the most common cause of death, and is due to failure of the donor immune system to eliminate residual disease. The immune cells most responsible for clearing leukaemia are T cells. T cells are often dysfunctional at relapse, and leukaemia is frequently able to evade them. Understanding why T cells become dysfunctional, and how AML escapes them, is critical to the development of new treatments that re-establish successful immune responses to treat or prevent relapse. Identifying patients with early immune dysfunction is also necessary to allow appropriate targeting of novel therapies. T-cell dysfunction occurs in many cancers and treatments that re-invigorate T cells have revolutionised cancer care. However, these therapies cause significant toxicity when given to transplant patients. Because there are many potential causes of T-cell dysfunction, it is important to identify those most relevant to the T cells that fight leukaemia, in order to target them without causing unacceptable side effects. To understand how donor T cells become dysfunctional, we will study the expression of genes and the structure of DNA in thousands of individual T cells from patients with AML relapse after transplant. This will allow us to explore in detail the changes that occur as T cells become dysfunctional and identify the major drivers of dysfunction in patients. Targeting these processes will then form the basis of novel therapeutic strategies to treat or prevent post-transplant relapse. AML frequently displays proteins that are involved in the activation of T cells, called MHCII. Expression is often lost at post-transplant relapse and this reduces the ability of leukaemia to activate T cells, providing a mechanism of immune evasion. How MHCII proteins are regulated in AML is not known. AML is a cancer of the blood-forming cells of the bone marrow. Through a process termed differentiation these cells normally give rise to the mature cells found in blood, some of which strongly express MHCII. This process becomes blocked in AML, but can be re-established by a recently developed class of drugs called LSD1 inhibitors. Using leukaemia and T cells isolated from patient samples, we will investigate the ability of these drugs to drive MHCII expression in AML and promote T-cell activation. LSD1 inhibitors are currently in clinical trials for AML, providing a clear pathway to clinical application, should our results support their use for post-transplant relapse. Before novel preventative therapies can be given to patients, those at risk of relapse must be identified. Recent studies suggest that early detection of dysfunctional T cells may predict relapse. Changes in the protein content of blood have also been observed that reflect the activity of T cells against leukaemia. Manchester is home to the Stoller Centre, Europe's largest clinical proteomic facility. We are able to analyse thousands of patient samples and track small changes in the concentration of hundreds of plasma proteins. We have established a study to collect blood samples at multiple time points from 300 transplant recipients. We will use these samples to identify changes in the protein content of blood and the properties of T cells that precede AML relapse, in order to develop new predictive blood tests. Overall, this study will identify the major drivers of immune dysfunction and leukaemic immune evasion that lead to AML relapse after stem cell transplantation. Our results will inform new therapeutic strategies for treating or preventing disease recurrence. We will also develop new blood tests that predict AML relapse, allowing therapeutic targeting of at-risk individuals and improving transplant outcomes.

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