NIHRDataInsights/HRCSData huggingface dataset:
Title: Preclinical development & CRUKD/15/001 A Cancer Research UK First in Human Phase I trial of 1RG CART, anti-GD2 chimeric antigen receptor transduced T-cells, in paediatric patients with relapsed or refractory neuroblastoma.
Funder: Cancer Research UK

Abstract: Neuroblastoma is the commonest extracranial solid cancer of childhood. The majority of children present with advanced disease at diagnosis. Despite marked intensification of therapy, less than 40% of high-risk patients will be long-term survivors. Administration of cancer-specific T-cells has shown dramatic efficacy in treating resistant cancers, but until recently, it has been impossible to readily generate neuroblastoma-specific T-cells. Using genetic engineering methods, it is now possible to introduce chimeric antigen receptors (CARs) into autologous T-cells rendering them specific for an antigen they would not normally react to. By nature, T-cells not only directly kill target cells; they can extravasate, penetrate a core of tumour, proliferate and secrete inflammatory cytokines at sites of disease. Consequently, engineered T-cells have a distinct therapeutic potential above that of monoclonal antibodies. Neuroblastoma has an ideal cancer antigen target for this approach, a ganglioside (disialoganglioside, GD2) which is expressed on almost all neuroblastoma tumours. We have recently reported a clinical study in Texas Children?s Hospital where administration of CAR-engineered GD2-specific T-cells resulted in clinical responses in 4 out of 11 patients with relapsed/refractory disease._x000D_ _x000D_ Since this study, we and others have continued to develop the field: we have demonstrated that inclusion of a co-stimulatory domain into the CAR results in T-cells which not only kill neuroblastoma cells, but proliferate and secret inflammatory cytokines in response. Further, we have refined our vector and receptor for improved expression levels, safety and reduced immunogenicity of the transgene. In addition, we have developed a safety switch which will allow selective depletion of adoptively administered T-cells in the face of unacceptable toxicity by administration of Rituximab. Finally, work by others has established that administration of lymphodepleting chemotherapy before giving cancer-specific T-cells improves their expansion and function._x000D_ _x000D_ We propose to build on our experience with engineered T-cell therapy in neuroblastoma and incorporate these new developments in a phase I/II dose escalation study of GD2 specific T-cells as treatment for relapsed/refractory neuroblastoma. We will evaluate safety, persistence and expansion of GD2-CAR engineered T-cells, as well as measuring effects on tumour burden. We request funding to complete our preclinical efficacy data in a small animal model of neuroblastoma, to scale up the production process of autologous GD2-CAR engineered T-cells and implement the phase I study.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Inequalities in cancer outcomes - Studentship
Funder: Cancer Research UK

Abstract: Background Despite the implementation of successive comprehensive cancer policy initiatives, cancer survival in England remains lower than in most comparably wealthy countries, and wide sociodemographic inequalities in cancer survival persist. These initiatives have largely emphasised the importance played by individual (tumour and patient) characteristics on these inequalities. We have however shown that patient characteristics (e.g. comorbidities) explained little of the sociodemographic inequalities in cancer care and survival. We have also shown that inequalities exist even on a stage-by-stage basis and that more advanced tumour stage caused only part of these inequalities. The question now is how to address these inequalities. Aims of the programme Our ultimate aim is to reduce these inequalities. Through a series of projects, we will focus on the multidimensional interplay between the (sociodemographic and clinical) characteristics of the patients and the healthcare system components. Understanding the patient-system interplay along the cancer patient pathway and its role on inequalities in outcomes will inform the development of interventions and policies for ensuring that all patients benefit from improvements in cancer care, regardless of their sociodemographic background. The studentship The contribution of a full-time doctoral student is immense, as they will be tasked to investigate specific research questions in depth adding significant value to aspects of the programme.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: CANCER AND NEOPLASMS
Title: Clinical and biological factors associated with relapse and length of survival following relapse in UK neuroblastomas
Funder: The Little Princess Trust

Abstract: Background Despite advances in neuroblastoma therapy relapse occurs in around 50% of patients with high risk neuroblastoma (50% of all neuroblastomas) who are then incurable in the vast majority of cases. It has previously been reported that time from diagnosis and the presence of MYCN amplification are important determinants of the length of survival following relapse but we hypothesise there are many other clinical and biological factors that are important. Aims In this combined epidemiological and genetic study we will: (1) Identify all UK and Ireland patients with relapsed/refractory neuroblastoma since 2000 and identify clinical and biological factors associated with relapse and length of survival following relapse. (2) Identify all patients treated on the recently closed European high risk neuroblastoma trial (HRNBL-1) with relapsed/refractory disease and compare their tumour genetics with cases that have not relapsed within 5 years. Expected Outcomes These studies will identify the genetic and clinical factors which predict relapse and length of survival after relapse, and provide valuable UK and Ireland data on relapsed neuroblastoma to compare with elsewhere in the world. This project will lead to patient benefit within the next 5 years.

Lay abstract: Background Despite advances in neuroblastoma treatments, relapse (cancer returning) occurs in around 50% of patients with high risk neuroblastoma (50% of all neuroblastomas) who are then incurable in the vast majority of cases. It has previously been reported that time from diagnosis to relapse and the presence of many copies of the MYCN oncogene ( a cancer causing gene) are important determinants of the length of survival following relapse. We hypothesise there are many other clinical and genetic factors that are important in how long a patient survives after relapse. Aims In this combined epidemiological and genetic study we will: (1) Identify all UK and Ireland patients with relapsed neuroblastoma since 2000 and identify clinical and biological factors associated with relapse and length of survival following relapse. (2) Identify all UK patients treated on the recently closed European high risk neuroblastoma trial (HR-NBL1) with relapsed or refractory (cancer not responding to treatment) disease and determine how their biology differs from those who have survived 5 years without relapse. Expected Outcomes These studies will identify new biological markers to predict relapse and length of survival after relapse and provide valuable UK and Ireland data on relapsed neuroblastoma to compare with other studies carried out elsewhere in the world. This project will lead to patient benefit within the next 5 years.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: Understanding the mechanisms and benefit risk of aspirin chemoprevention of cancer through population research - Aspirin for Cancer Prevention Collaboration (AfCPC) - Catalyst Award - Studentship
Funder: Cancer Research UK

Abstract: Background: Aspirin reduces the risk of colorectal cancer mostly likely gastric and oesophageal cancers. A major review concluded that regular aspirin use would reduce the incidence of cancer (all sites combined) by 7% (women) to 9% (men): a result directly observed in the large CPS-II cohort. Aspirin use has also been associated with better survival in cancer patients (Add-aspirin trial). Within colorectal cancer patients from the Nurses’ Health Study, it was shown that the beneficial effect of aspirin on colorectal cancer specific death was only seen in patients with mutated-PIK3CA (HR=0.18) and not in wild-type patients (HR=0.96; P=0.009 for interaction). Despite these findings, few organisations recommend aspirin prophylaxis. There are concerns about side-effects (including upper GI bleeds) and the harms and benefits are thought by some to be too finely balanced for widespread population use. There is also a lack of knowledge, which prevents further progress in translating the potential benefit of aspirin into a public health intervention. There is little data on the optimal dose of aspirin and little understanding of the mechanisms by which aspirin reduces cancer risk. Aims: The aim of the collaboration is to investigate the mechanisms of action’ whereby aspirin prevents cancer. The collaboration will enable for the first time a diverse group of investigators to work together to coordinate mechanism discovery in cohorts with detailed information on aspirin use as well as expertise in molecular epidemiology, cancer chemoprevention, clinical trials, biostatics and the translation of various omics assays into population research studies. We will also study aspirin’s adverse effects and identify specific biomarkers. Finally we will research the psychological, sociological and related barriers to the use of aspirin in the primary prevention of cancers. Methods: The collaboration will enable a concerted effort to identify biomarkers using RNA expression profiling, plasma proteomic inflammation markers, and next generation sequencing (DNA methylation and somatic SNV/indels) in large cohorts with aspirin use (NHS, Add-aspirin, CaPP and HEAT) and also CRISPR-Cas9 Gene Editing and functional screening. How the results of this research will be used: A major achievement will be to set up an infrastructure to allow future development and planning of large international trials of cancer chemoprevention using aspirin with a novel efficient design and exploiting the mechanistic knowledge learnt from this collaboration. The collaboration would support inter-disciplinary and international PhD and post-doctoral training to produce future leaders in population research, by facilitating exchange visits between collaborating institutions.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS
Title: Investigating Rho-kinase (ROCK) in melanoma progression and therapy response
Funder: Cancer Research UK

Abstract: Prof Victoria Sanz-Moreno, studies melanoma, the 5th most common cancer in the UK. Metastasis- the spread of cancer cells around the body- is a key problem for treating melanoma patients. Once melanoma has spread it is much more difficult to treat. The other major hurdle for melanoma treatment is resistance to current therapies. Sanz-Moreno’s group has already identified a molecule called ROCK as a key player in the spread of melanoma cells. By understanding more about how ROCK works, our group hopes to work out if it’s possible to target it with drugs. Moreover, with this Award, we will understand if inhibiting ROCK alongside other drugs that interact with the immune system is the best way to help melanoma patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Cancer Research UK Children's Brain Tumour Centre of Excellence (CRUK-CBTCE)
Funder: Cancer Research UK

Abstract: Background: Brain tumours remain the commonest cause of cancer-related death in children. Limited progress in these diseases relates directly to the use of inaccurate preclinical pipelines that fail to identify drugs with activity in patients. Accurate preclinical pipelines are especially important for rare cancers, such as paediatric brain tumours, that have small patient populations available for study. Thus, curing all children with brain tumours will require a new approach that leverages a deep understanding of tumour biology to design disease-specific therapies. Aims: The vision of the Cancer Research UK Children’s Brain Tumour Centre of Excellence (CRUK-CBTCE) is to transform the way the world develops treatments for children with brain tumours. Its mission is to forge an innovative four-stage pipeline that generates curative treatments for children with brain tumours, wherever they live. Hosted at the CRUK Cambridge Major Centre and The Institute for Cancer Research, London, the CRUK-CBTCE will convene a critical mass of expert personnel, infrastructure and global collaborations in paediatric brain tumour biology, medicinal chemistry, pharmacology, and preclinical and clinical trials. Our goal is to develop full clinical trial designs of three new or repurposed drugs by the end of the first cycle of funding. Methods: Our research strategy is centred on our biology and drug discovery pipeline. Pipeline-Stage 1 will advance understanding of the basic biology of paediatric brain tumours by developing and studying highly-accurate mouse models. Pipeline-Stage 2 will study these models and human tumours to identify and validate cell pathways critical for maintaining the malignant phenotype that may serve as therapeutic targets. Pipeline-Stage 3 will identify, prioritise and optimise inhibitors of lead targets validated in Stage 2. And Pipeline-Stage 4 will test lead candidates emerging from the pipeline in our preclinical mouse hospital in the context of ‘standard-of-care’ combination neurosurgery, fractionated irradiation and conventional chemotherapy. The CRUK-CBTCE will also unite the CRUK-CBTCE membership with an international community of aligned experts through the world’s first ‘webinar-based’ International Children’s Brain Tumour Board and serve as the Conference Secretariat for the ongoing Gordon Conference-style ‘Paediatric Brain Tumour in the Mountains’ meetings. As part of its educational initiatives the CRUK-CBTCE will establish a new series of Paediatric Brain Tumour Summer Schools and train PhD students. Output: Through this international, collaboration and education structure, the CRUK-CBTCE will become the global leader in preclinical paediatric brain tumour innovation, rapidly accelerating the development of new cures.


Research activity codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Full Duration Non-clinical Studentship - Accelerator Award A26822 "Multi-modal clinical testing of prostate cancer patient plasma"
Funder: Cancer Research UK

Abstract: Precision medicine in oncology requires broadly-applicable molecular characterisation of tumours. In contrast to tissue, liquid biopsies are minimally disruptive and can be obtained repeatedly, providing real-time molecular data. We aim to broaden the clinical utility of plasma analyses for risk stratification and treatment selection, monitoring and characterisation of resistance by increasing the amount and quality of information obtained. We have assembled a team that includes prostate cancer specific expertise on all key components (molecular, clinical, genomics, epigenetics, vesicles, liquid biopsies) and extends to multiple hospitals and clinical trial cohorts with the dual aim of ensuring both prospective enrolment of advanced prostate cancer patients to answer specific clinical questions and to result in up-and-running liquid biopsy tests at multiple institutions by end of the project. Approaches established will also have utility in plasma analyses in other cancer types. Our team will: 1. Implement novel computational approaches and targeted design strategies to accurately quantitate commonly recurring point mutations and copy number changes, including mono- and bi-allelic deletions at low tumour purities. 2. Integrate these genomic data with readouts of methylation status and use clinically applicable approaches for exosome isolation and analyses to obtain information on mRNA and protein expression. 3. Establish a cloud-based computational pipeline to enable standardized analysis across our network and with external collaborators. 4. Independently clinically qualify the multi-modal testing in plasma samples collected in multi-centre prostate cancer clinical trials representative of different stages in the disease spectrum.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/17/010 Intravenous VCN-01 Ahead of Planned Surgical Resection for High Grade Brain Tumours (Jointly funded by Cancer Research UK, The Brain Tumour Charity and Brain Tumour Research and Support Across Yorkshire)
Funder: Cancer Research UK

Abstract: Oncolytic virus immunotherapy utilises replicating viruses to generate tumour-directed immune responses and selectively kill tumour cells. For patients with brain tumours, concerns that the blood-brain barrier may inhibit oncolytic virus access to tumour have thus far limited attempts at intravenous administration. Current techniques utilising intratumoural injection require careful patient selection and technically challenging neurosurgery.VCN-01 is a genetically modified oncolytic adenovirus. VCN-01 has been tested in several clinical trials in patients with cancer, with an established top dose. Importantly, our laboratory and clinical data indicate that oncolytic viruses access brain tumours following intravenous infusion, and increases expression of the immune checkpoint protein PD-L1 on glioma cells. The primary objectives of this window of opportunity trial are to assess the presence of VCN-01 in resected brain tumours following intravenous infusion in patients, and to determine safety. Secondary objectives are exploratory and will include assessment of the peripheral blood and tumour immune response. Immune-mediated anti-cancer effects in resected brain tumours will be correlated to potential peripheral blood immune biomarkers. This is an open-label, non-randomised, single centre study of VCN-01 given intravenously to patients prior to planned surgery for recurrent high grade primary or metastatic brain tumours. Up to 12 patients will be recruited, each to be administered a single intravenous infusion of VCN-01. Resected tumours will be assessed for the presence of VCN-01 by several techniques such as immunohistochemistry, in-situ hybridization, immunogold electron microscopy and qPCR. Patient tumour and blood samples will be analysed to detect immune cell activation, anti-cancer immune function, cytokine secretion and upregulation of immune checkpoints, to help guide future checkpoint blockade combination therapy. This study will identify whether intravenous VCN-01 accesses brain tumours, and determine the potential for sequential combination with immune checkpoint blockade in a future Phase 1-2 study.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Understanding the competition between healthy and malignant haematopoiesis within the bone marrow microenvironment: from mechanisms to targets - Studentship
Funder: Cancer Research UK

Abstract: Background. Acute myeloid leukaemia (AML) is an aggressive disease that invades and grows within the bone marrow, outcompeting healthy haematopoiesis and causing multiple blood cytopenias. Chemotherapy, often combined with bone marrow (BM) transplantation, is largely successful as primary treatment. However, a significant number of patients does not recover healthy haematopoiesis despite showing reduced leukaemia burden. These patients have a higher risk to develop relapse, which is typically resistant to treatment, and have reduced survival compared to patients with complete blood recovery. Multiple haematopoietic malignancies are known to remodel the bone marrow microenvironment in their favour and at the expenses of healthy haemaotpoiesis, but the mechanisms mediating this transformation remain unclear. Haematopoietic stem cells (HSCs) maintain the turnover of all blood cells from specialised niches within the bone marrow microenvironment and survive the longest, albeit functionally inhibited, in AML-burdened mice and patients. Understanding what allows them to survive and to restart regeneration following leukaemia treatment is critical to improve AML therapies, especially for those patients that fail to restore healthy haematopoietic counts following chemotherapy. Aims. I will address three main aims: 1. To identify the mechanisms leading to loss of BM stroma. 2. To identify the mechanisms leading to loss of haematopoietic stem cells and their progeny. 3. To understand the dynamics of BM regeneration following leukaemia treatment and develop strategies that could improve it. Methods. I will drive a multidisciplinary approach, stemming from my expertise in cutting-edge bone marrow intravital microscopy, to test multiple hypotheses about the cellular and molecular processes driving AML-induced bone marrow stroma and haematopoietic loss, followed by their regeneration. Genetic and pharmacological approaches will test the role of multiple candidate drivers of these transformations. Multiplex immunostainings of murine samples will provide spatio-temporal and molecular detail and similar analyses of human trephine biopsies will validate our findings. How the results of this research will be used. An improved understanding of how AML hijacks the BM, and how the haematopoietic system regenerates post chemotherapy (including following BM transplantation) will likely uncover novel pathways for therapeutic intervention to both improve post-therapy haematopoietic recovery and decrease the likelihood of relapse. The novel immunostainings of human trephine biopsies will reveal links between microenvironment remodelling and the patients’ regenerative capacity and will have the potential to become valuable diagnostic tools, guiding therapeutic decisions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS