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Expansion cohorts in phase 1 oncology trials: a systematic review of their design, implementation and outcomes.
No full textThe urgent need for drug development for cancer patients and the complexity of novel therapies have led to the increasing importance of expansion cohorts (EC) within phase 1 trial design. We conducted a systematic review of oncology phase 1 trials with EC published from 2019 to 2023. The objective was to assess the characteristics, purpose and outcomes of EC. A mixed-effects meta-regression model was conducted to analyse response rates. 479 published phase 1 trials with EC were included (median number of EC patients per trial: 27). The EC objective was stated in 55.7% of studies (76.8% safety, 16.5% dosing, 25.8% pharmacokinetics, 22.1% pharmacodynamics, 77.5% preliminary efficacy). 117 trials (24.4%) included a statistical justification plan. The mean Overall Response Rate (ORR) was 20.2% in solid tumours and 46.8% in haematological malignancies. Among drug classes, Antibody-drug conjugates showed the highest ORR (32.1%). Higher ORR was significantly associated with combination therapies, haematological trials, trials with statistical justification for EC sample size and trials not containing Immunotherapy. EC have evolved to become large dynamic studies assessing both preliminary efficacy and safety. This study highlights the importance of clearly stated EC objectives and sample size justification to enhance the rigour and interpretability of early-phase evidence
Baseline characteristics predicting lower return rates of missing patient-reported quality of life data over 5 years: evidence from the IMPORT HIGH and IMPORT LOW breast cancer radiotherapy trials.
No full textBACKGROUND AND PURPOSE: Long-term patient reported outcomes (PROs) from questionnaires are important to capture late adverse effects in breast cancer treatment. Declining return rates over time may introduce selection bias and reduce robustness of results. Using data from two trials which had collected data prospectively, we investigated factors associated with non-return of PROs at 5 years. We also investigated which questions were more likely missed in PROs. MATERIALS AND METHODS: IMPORT HIGH (ISRCTN47437448) and IMPORT LOW (ISRCTN12852634) investigated different radiotherapy treatments for breast cancer patients with high and low ipsilateral breast tumour relapse risk respectively. Both trials had PRO sub-studies with similar design, using questionnaires such as EORTC QLQ-C30, QLQ-BR23 and Body Image Scale. We used univariable and multivariable logistic regressions for the analysis. RESULTS: The return rate for PROs was 99.5 % (1034/1039) at baseline and 81.4 % (766/941) at year 5, 100 % (1257/1257) and 84 % (974/1165) for IMPORT HIGH/LOW respectively. Participants with moderate/severe depression/anxiety at baseline were more likely to miss year-5 response: IMPORT HIGH 16 % with depression/anxiety, OR = 1.60, CI = [1.03-2.49]; IMPORT LOW 9 % with depression/anxiety, OR = 2.62, CI = [1.66-4.14]. In multivariable analysis, age, smoking status, depression/anxiety, and ethnicity were significant predictors of missing PRO returns in IMPORT HIGH while depression/anxiety, relationship status and deprivation in IMPORT LOW. Participants who missed sexual functioning questions initially were more likely to continue missing them (OR = 1.02, CI = [1.00-1.03] IMPORT HIGH; OR = 1.02, CI = [1.01-1.02] IMPORT LOW). CONCLUSION: Participants who were younger, more deprived, smoked at baseline, had depression/anxiety may require targeted support to return PRO during follow-up. Sensitive questions need 'Prefer not to say' or 'Not applicable' options available and require further work to optimise wording
Evaluating the Effectiveness of a Novel Mobile Clinical Unit (the Man Van) in Addressing Health Inequalities in Prostate Cancer
No full textProstate cancer is the most common male cancer in the United Kingdom and the second most common worldwide. Significant health inequalities exist with Black men and those from socioeconomically deprived backgrounds disproportionately affected by late-stage diagnoses and poorer outcomes.This thesis evaluates effectiveness of the Man Van, a novel mobile clinical unit designed to address inequalities in prostate cancer. The research is composed of multiple components: an introduction into prostate cancer and health inequalities, a systematic review of mobile clinical units for prostate cancer, the Man Van pilot study to establish feasibility, development of a novel patient experience questionnaire, an up-scaled and optimised phase 2 of the Man Van evaluated with mixed-methods data including qualitative interviews with participants and stakeholders of the project and a health economics analysis. Sub-studies were conducted evaluating the use of point-of-care (POCT) prostate-specific antigen (PSA) testing and polygenic risk scores (PRS) for prostate cancer both through the Man Van.The findings demonstrate that the Man Van successfully engaged populations traditionally underserved by healthcare, with high proportions of participants from ethnically diverse and socioeconomically deprived communities. The service facilitated the early detection of clinically significant prostate cancers, as well as diabetes, hypertension and other health conditions. Patient-reported data revealed strong satisfaction and trust in the model, with the health economics evaluation demonstrating cost-effectiveness when compared to PSA testing within primary care. Stakeholder interviews provided further context including facilitators and barriers for implementing a more widespread model. POC testing showed feasibility but the accuracy was insufficient to support its use at present. PRS showed a modest increase in detection rates within this high-risk population.Collectively, this research supports the use of the Man Van to transform early cancer detection strategies and address entrenched health inequalities both nationally and globally
Programmed cell death ligand 1 (PD-L1) expressing myeloid cells and their relevance to cancer immunotherapy
No full textIntroduction:
Myeloid cells are increasingly being recognised as playing a key role in antitumour
adaptive immunity, rather than their previously thought, over simplified
role in innate immunity. Programmed cell death ligand 1 (PD-L1) has recently
been shown to be expressed on myeloid subsets such as neutrophils and
monocytes, raising questions over the subsequent implications in immune
suppression and immune checkpoint inhibitor (ICI) efficacy. This thesis presents
an exploratory, multi-modal analysis of myeloid checkpoint expression in the
context of cancer immunotherapy, with a particular focus on PD-L1 expression
across both peripheral blood and intra-tumoural compartments.
Methods:
Combining multiparametric flow cytometry, longitudinal sampling and multiplex
immunohistochemistry (mIHC), we conducted an exploratory analysis
investigating the role of PD-L1+ neutrophils and monocytes (PD-L1+NM) in
both the peripheral blood and tumour microenvironment (TME) of patients with
skin and renal cancers undergoing immunotherapies. Patients were assessed
across cohorts including ICI and tumour infiltrating lymphocyte (TIL) therapies.
Additional myeloid markers LOX-1, VISTA and CXCR2 were investigated for
deeper phenotypic profiling. T cell subset correlation and high dimensional
clustering were performed to identify dynamic longitudinal changes.
Results:
PD-L1+NM were elevated in patients with cancers compared to controls and
increased during periods of systemic inflammation and immune-related adverse
events. Peripheral blood myeloid and T cell compartments revealed a
significant correlation between T cell activation and PD-L1+NM post ICI and TIL
infusion. Peripheral blood PD-L1+NM findings were not found to correlate well
with TME myeloid infiltrate. Finally, LOX-1+ polymorphonucler myeloid derived
suppressor cells (PNM-MDSC’s) were enriched in the periphery post TIL
lymphodepletion, and within the TME at baseline
NSD2 targeting reverses plasticity and drug resistance in prostate cancer.
No full textLineage plasticity is a cancer hallmark that drives disease progression and treatment resistance1,2. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE)3-5. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase6. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice7 that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting of NSD2 reverts CRPC-NE to adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated and responses to the AR inhibitor enzalutamide are restored. Pharmacological inhibition of NSD2 with a first-in-class small molecule reverses plasticity and synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting of NSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC that are currently recalcitrant to treatment
Improving MRI Image Reconstruction for Radiotherapy on an MR-Linac
No full textContext: For hard-to-treat pancreatic cancers, respiratory motion leads to increased radiotherapy doses to the surrounding organs, which limits the dose which can be safely delivered to the tumour. The MR-Linac, which combines an MRI scanner and a linear accelerator, aims at improving pancreatic cancer treatment by visualising the position and motion of the tumour before and during treatment. However, the current clinical workflow can only determine the tumour motion using limited 2D cine imaging. Challenge: 4D-MRI representing the respiratory-motion through either an average respiratory-cycle (respiratory-correlated) or through time (time-resolved) could improve the motion estimates, but 4D-MRI images are not implemented clinically due to high reconstruction times and limited temporal resolutions. Additionally, improving the image quality on the MR-Linac would improve the treatment of pancreatic tumours by reducing uncertainties in the tumour and organs at risk positions. Aims: To improve the quality of images acquired on the MR-Linac, decrease the reconstruction time of respiratory-correlated and time-resolved4D-MRI images below the five minutes required for their adoption in the MRLinac clinical workflow, and to increase the temporal resolution of 4D-MRI.Methods: A novel reconstruction framework implemented in Julia was developed to accelerate 4D-MRI reconstructions using the XD-GRASP and GRASP-Pro algorithms for respiratory-correlated and time-resolved 4D-MRI reconstruction, respectively. An acquisition based on Cartesian spirals (CASPR) designed for 4D-MRI was implemented and compared against the current radial acquisition used clinically. Data acquired from previous radiotherapy fractions were combined with data from the current fraction to improve image quality. Results: Respiratory-correlated and time-resolved 4D-MRI images were reconstructed from radial data under one and four minutes, respectively. Improved reconstruction times of 30s and less than 2:30 minutes were achieved for CASPR, achieving a 500ms time resolution across a large field of view. Images reconstructed using data from previous fractions demonstrated improved contrast but required longer reconstructions
Multimodal profiling of cancer-associated fibroblasts in Muscle-invasive bladder cancer
No full textBackground: Cancer-associated fibroblasts (CAFs) are a stromal population in the tumour
microenvironment with pro-tumour and immunosuppressive functions. The role of CAFs in muscle
invasive bladder cancer (MIBC) is poorly understood. The thesis aims to characterise CAFs in this
setting and address the hypothesis that CAF enrichment is associated with radiotherapy resistance via
immune and non-immune mechanisms.
Methods: A multimodal approach was adopted combining transcriptomic analysis with multiplex
immunofluorescence (mIF) and matrix fibre tracing to study the spatial organisation of distinct CAF
populations and to determine their association with CD8+ T cells, cancer cells and the extracellular
matrix.
Results: Using transcriptional signatures, stromal high, CAF-enriched tumours were associated with
poor survival outcomes for MIBC patients treated with radiotherapy in the BC2001 trial. Differential
gene expression and pathways analysis revealed that the stromal high group was associated with
chronic inflammation and extracellular matrix remodelling. Quantification of mIF images highlighted
that PDPN+ CAFs were the most abundant population in the stromal compartment however, CAF
composition was variable across consensus molecular subtypes. FAP+ CAFs were enriched in
Basal/Squamous bladder tumours. Assessment of the CD8+ T cell infiltrate revealed that CD8+ T cells
were frequently located in the stromal regions, with minimal invasion into tumour nests. Spatial analysis
highlighted that fibroblast subtypes were arranged in distinct regions, with FAP+ CAFs forming cellular
communities with CD8+ T cells. Analysis of extracellular matrix fibres resulted in the identification of 4
clusters associated with unique arrangements of matrix fibres. Combining mIF data with matrix clusters
highlighted a significant association between FAP+ CAFs and the formation of a dense extracellular
matrix.
Conclusions: CAF enrichment in the baseline tumour microenvironment of MIBC is significantly
associated with poor responses to radiotherapy. Moreover, FAP has emerged as an important marker
of CAFs associated with CD8+ T cell sequestration in the stroma and the formation of a dense
extracellular matrix. Taken together, this data suggests that FAP+ CAFs may contribute to therapy
resistance via immunosuppressive and matrix remodelling functions however, further work is required
to determine the molecular mechanisms underlying these observations to effectively target them in the
future
Exploring phenotypic plasticity as a mechanism of early adaptation to treatment in neuroblastoma
No full textNeuroblastoma is a paediatric tumour characterised by extensive clinical heterogeneity, ehich spans from spontaneous regression to therapeutic resistance or relapse. Much of this diverse clinical presentation, is thought to be driven by phenotypic plasticity and heterogeneity in tumour cell populations. Phenotypic plasticity is a key mechanism through which tumour cells may adapt and survive changing environments by changing their phenotype without altering their genotype. Recent studies have emphasized the need to understand the molecular factors controlling phenotypic
plasticity, as a means to generate more effective therapies that improve treatment outcomes in neuroblastoma patients. To this end, within this thesis I explored the role of phenotypic plasticity as a mechanism to early adaptation to treatment in neuroblastoma. Using molecular and functional characterisation assays and drug response assays, I demonstrate the clinical and molecular
implications of phenotypic composition in neuroblastoma. Utilising cellular barcoding technologies and single cell resolution transcriptomics, I demonstrated that phenotypic plasticity is be enriched following neuroblastoma treatment responses. Experimental evolution and reaction norms methods
demonstrated phenotypic plasticity was a heterogeneous trait in neuroblastoma populations. Using single nuclei multiomics technologies, I characterised the molecular features defining plastic
neuroblastoma cells and identified potential TFs and pathways regulating phenotypic plasticity. Finally, I defined regulatory developmental pathways which regulate phenotypic plasticity during treatment response in neuroblastoma
Investigation of bone marrow failure in acute myeloid leukaemia through targeted sequencing
No full textOur group has shown that CD34-negative AML induces haematopoietic stem cells
(HSCs) into a quiescent state, blocking differentiation. If this holds for all AMLs, all
patients should present with pancytopenia. However, some exhibited bi/unilineage
cytopenia.
This thesis explored two key questions regarding bone marrow failure in AML. First, I
investigated the origin of residual mature cells in CD34+ (n=40) and CD34- AML
(n=12) through genotyping to understand why not all patients present with
pancytopenia. I also enumerated putative EPCR+ (Endothelial Protein C Receptor)
HSCs in 108 AML samples to investigate HSC depletion or preservation.
Two-thirds of neutrophils and half of erythroblasts derived from differentiation of
leukaemic blasts, while some mature cells originated from pre-leukaemic and normal
HSCs. Most patients whose neutrophils shared all mutations with blasts had
preserved neutrophils (>1.8x10^9/l), whereas haemoglobin was not preserved
(>100g/l), regardless of erythroblast origin. Although 70% of megakaryocytes derived
from normal HSCs, only two patients had preserved platelets (>100x10^9/l).
Differences in origin of mature cells may explain uni/bilineage cytopenia in some
patients. We propose a new model of marrow failure for core binding factor (CBF)
AML that neutrophils arise from leukaemic blasts and megakaryocytes from normal
HSCs.
We developed a four-marker flow panel (CD34, CD38, CD33 and CD45RA) to identify
putative HSCs in CD34+ CD45RA+ AML, validated through functional assays and
genotyping. HSC fraction derived cells were free of leukaemia mutations, whereas
those from blasts fraction harboured mutations.
HSC enumeration in AML remission samples showed that patients in complete (CR)
and partial remission (PR) had comparable EPCR+ HSCs to control (lymphoma
staging) marrows, while those in CRi (CR with incomplete count recovery) exhibited
significantly lower numbers. If validated, these findings suggest HSC depletion may
contribute to haematopoietic failure in CRi patients post induction chemotherapy. This
may allow modification of therapy e.g. earlier marrow transplant
The tumour histopathology "glossary" for AI developers.
No full textThe applications of artificial intelligence (AI) and deep learning (DL) are leading to significant advances in cancer research, particularly in analysing histopathology images for prognostic and treatment-predictive insights. However, effective translation of these computational methods requires computational researchers to have at least a basic understanding of histopathology. In this work, we aim to bridge that gap by introducing essential histopathology concepts to support AI developers in their research. We cover the defining features of key cell types, including epithelial, stromal, and immune cells. The concepts of malignancy, precursor lesions, and the tumour microenvironment (TME) are discussed and illustrated. To enhance understanding, we also introduce foundational histopathology techniques, such as conventional staining with hematoxylin and eosin (HE), antibody staining by immunohistochemistry, and including the new multiplexed antibody staining methods. By providing this essential knowledge to the computational community, we aim to accelerate the development of AI algorithms for cancer research