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Targeting Endo180 with an antibody-drug conjugate for cancer treatment
No full textAntibody-drug conjugates (ADCs) are formed of an antibody attached to a cytotoxic drug via a linker which is cleaved upon internalisation of the ADC into the cell. This allows very toxic drugs to be directed to specific cells in the body. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate. Endo180 is highly expressed on many tumours of mesenchymal origin, including a large proportion of sarcomas. Endo180 is also upregulated on cancer-associated fibroblasts (CAFs) in the stroma of breast and other epithelial cancers. Previous work by our laboratory has demonstrated a tumour promoting and immune restrictive role of Endo180 CAFs.
The aim of this PhD was to assess the utility of targeting Endo180 with an ADC and the efficacy of an Endo180-ADC in both tumour cell-targeting and CAF-targeting contexts. In vitro characterisation established that an anti-Endo180 monoclonal antibody conjugated to the anti-mitotic agent, MMAE, via a cleavable linker, is rapidly internalised into target cells, causing cell death specifically in Endo180-expressing sarcoma cell lines. In a sarcoma tumour xenograft model, the Endo180-vc-MMAE ADC drove on target cytotoxicity resulting in tumour regression and a significant impairment of metastatic colonisation of the lungs, liver and lymph nodes. Investigation of this Endo180-vc-MMAE ADC in fibroblasts determined that whilst the fibroblasts were not as sensitive to the ADC, they were able to process the ADC and release free drug, killing surrounding tumours cells in a bystander effect.
This thesis proposes that an Endo180-ADC is a potential candidate for targeted therapy of solid mesenchymal tumours. Further studies are required to develop an antibody recognising mouse Endo180, which was unsuccessful during this PhD, in order to assess of off-tumour toxicities of an Endo180-ADC and to gain a better understanding of the efficacy of an Endo180-ADC targeting CAFs in animal models
Capturing longer term surgical outcome measures as part of routine care of breast cancer patients.
No full textINTRODUCTION: The transition away from routine clinical follow up after breast cancer towards imaging surveillance and patient-initiated contact limits opportunities for patients and doctors to communicate about the long-term effects of treatment. The ABS oncoplastic guidelines (2021) recommend that post-operative 2D images and patient-reported outcomes (PROMs) are routinely collected but give no guidance as to how best to implement this. METHODS: From December 2019 until March 2024, women due for their year 3 or 5 surveillance mammogram at The Royal Marsden Sutton site were invited to complete a BREAST-Q questionnaire and attend medical photography. Panel assessment of photographs was undertaken. Results were presented to the oncoplastic MDT, including summary PROMs and illustrative case presentations. Free-text comments were shared with the relevant teams. Associations between demographic or clinic-pathological factors and uptake were investigated. RESULTS: Of the 1211 women invited, 246 patients (20.3 %) completed BREAST-Q questionnaires, 182 (15.0 %) attended for medical photography and 114 (9.4 %) completed both. Uptake was not associated with age, ethnicity or surgical factors but patients with higher BMI were less likely to respond to the questionnaire. Patients who had undergone complex oncoplastic procedures were more likely to respond than those who had simple procedures. Patient-reported outcome results were in line with the published literature. CONCLUSION: Reviewing images with their paired PROMs and discussing free-text feedback was instructive for the team. Work is needed to identify barriers to patient participation and improve uptake to be representative of the overall patient population. Quantifying appearance in photographs would help summarise aesthetic outcome data
Complete Primary Pathological Response Following Neoadjuvant Treatment and Radical Resection for Pancreatic Ductal Adenocarcinoma.
No full textINTRODUCTION: Neoadjuvant treatment (NAT) for borderline (BD) or locally advanced (LA) primary pancreatic cancer (PDAC) is now a widely adopted approach. We present a case series of patients who have achieved a complete pathological response of the primary tumour on final histology following neoadjuvant chemotherapy +/- chemoradiation and radical surgery. METHODS: Patients who underwent radical pancreatic resection following neoadjuvant treatment between March 2006 and March 2023 at a single institution were identified by retrospective case note review of a prospectively maintained database. RESULTS: Ten patients were identified to have a complete primary pathological response (ypT0) on postoperative histology. Before treatment, five patients were considered BD and five were LA according to National Comprehensive Cancer Network guidelines. All patients underwent staging Computed Tomography (CT) and nine underwent 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET/CT) imaging, with a mean maximum standardized uptake value (SUVmax) of the primary lesion at 6.14 ± 1.98 units. All patients received neoadjuvant chemotherapy, and eight received further chemoradiotherapy prior to resection. Mean pre- and post-neoadjuvant treatment serum Ca19-9 was 148.0 ± 146.3 IU/L and 18.0 ± 18.7 IU/L, respectively (p = 0.01). The mean duration of NAT was 5.6 ± 1.7 months. The mean time from completion of NAT to surgery was 13.1 ± 8.3 weeks. The mean lymph node yield was 21.1 ± 10.4 nodes, with one patient found to have 1 lymph node involved. All resections were reported to be R0. The mean length of stay was 11.8 ± 6.2 days. At the time of analysis, one death was reported at 35 months postoperatively. Two cases of recurrence were reported at 16 months (surgical bed) and 33 months (pulmonary). All other patients remain alive and under active surveillance. The current overall survival is 26.6 ± 20.7 months and counting. CONCLUSIONS: Complete primary pathological response is uncommon but possible following neoadjuvant treatment in patients with PDAC. Further work to identify the common denominator within this unique cohort may lead to advances in the therapeutic approach and offer hope for patients diagnosed with borderline or locally advanced pancreatic ductal adenocarcinoma
Impact of on-trial IGRT quality assurance in an international adaptive radiotherapy trial for participants with bladder cancer.
No full textBACKGROUND AND PURPOSE: Radiotherapy trial quality assurance (RT QA) is crucial for ensuring the safe and reliable delivery of radiotherapy trials, and minimizing inter-institutional variations. While previous studies focused on outlining and planning quality assurance (QA), this work explores the process of Image-Guided Radiotherapy (IGRT), and adaptive radiotherapy. This study presents findings from during-accrual QA in the RAIDER trial, evaluating concordance between online and offline plan selections for bladder cancer participants undergoing adaptive radiotherapy. RAIDER had two seamless stages; stage 1 assessed adherence to dose constraints of dose escalated radiotherapy (DART) and stage 2 assessed safety. The RT QA programme was updated from stage 1 to stage 2. MATERIALS AND METHODS: Data from all participants in the adaptive arms (standard dose adaptive radiotherapy (SART) and DART) of the trial was requested (33 centres across the UK, Australia and New Zealand). Data collection spanned September 2015 to December 2022 and included the plans selected online, on Cone-Beam Computed Tomography (CBCT) data. Concordance with the plans selected offline by the independent RT QA central reviewer was evaluated. RESULTS: Analysable data was received for 72 participants, giving a total of 884 CBCTs. The overall concordance rate was 83% (723/884). From stage 1 to stage 2 the concordance in the plans selected improved from 75% (369/495) to 91% (354/389). CONCLUSION: During-accrual IGRT QA positively influenced plan selection concordance, highlighting the need for ongoing support when introducing a new technique. Overall, it contributes to advancing the understanding and implementation of QA measures in adaptive radiotherapy trials
Alveolar rhabdomyosarcoma with regional nodal involvement: Results of a combined analysis from two cooperative groups.
Get PDFBACKGROUND: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define a better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group (COG). METHODS: We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised ifosfamide + vincristine + dactinomycin + doxorubicin (IVADo), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531, it consisted of either vincristine + dactinomycin + cyclophosphamide (VAC) or VAC alternating with vincristine + irinotecan (VI). Local treatment was similar in both protocols. RESULTS: The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced Intergroup Rhabdomyosarcoma Study Group (IRS) and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49% (95% confidence interval [CI]: 39-59) and 44% (95% CI: 30-58), and overall survival (OS), 51% (95% CI: 41-61) and 53.6% (95% CI: 40-68) in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those with FOXO1-negative (49.3% vs 73%, P = .034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those with FOXO1-negative. CONCLUSIONS: The outcome of patients with ARMS N1 was similar in both protocols. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that different strategies of chemotherapy may have an impact in the outcome of this subgroup of patients
Joint ABS-UKCGG-CanGene-CanVar consensus regarding the use of CanRisk in clinical practice.
No full textBACKGROUND: The CanRisk tool, which operationalises the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is used by Clinical Geneticists, Genetic Counsellors, Breast Oncologists, Surgeons and Family History Nurses for breast cancer risk assessments both nationally and internationally. There are currently no guidelines with respect to the day-to-day clinical application of CanRisk and differing inputs to the model can result in different recommendations for practice. METHODS: To address this gap, the UK Cancer Genetics Group in collaboration with the Association of Breast Surgery and the CanGene-CanVar programme held a workshop on 16th of May 2023, with the aim of establishing best practice guidelines. RESULTS: Using a pre-workshop survey followed by structured discussion and in-meeting polling, we achieved consensus for UK best practice in use of CanRisk in making recommendations for breast cancer surveillance, eligibility for genetic testing and the input of available information to undertake an individualised risk assessment. CONCLUSIONS: Whilst consensus recommendations were achieved, the meeting highlighted some of the barriers limiting the use of CanRisk in clinical practice and identified areas that require further work and collaboration with relevant national bodies and policy makers to incorporate wider use of CanRisk into routine breast cancer risk assessments
Structural and quantum chemical basis for OCP-mediated quenching of phycobilisomes.
No full textCyanobacteria use large antenna complexes called phycobilisomes (PBSs) for light harvesting. However, intense light triggers non-photochemical quenching, where the orange carotenoid protein (OCP) binds to PBS, dissipating excess energy as heat. The mechanism of efficiently transferring energy from phycocyanobilins in PBS to canthaxanthin in OCP remains insufficiently understood. Using cryo-electron microscopy, we unveiled the OCP-PBS complex structure at 1.6- to 2.1-angstrom resolution, showcasing its inherent flexibility. Using multiscale quantum chemistry, we disclosed the quenching mechanism. Identifying key protein residues, we clarified how canthaxanthin's transition dipole moment in its lowest-energy dark state becomes large enough for efficient energy transfer from phycocyanobilins. Our energy transfer model offers a detailed understanding of the atomic determinants of light harvesting regulation and antenna architecture in cyanobacteria
Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial.
Get PDFBACKGROUND: First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data. METHODS: This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population. RESULTS: A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. CONCLUSIONS: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC
U-PRO-CRM: designing patient-centred dose-finding trials with patient-reported outcomes.
No full textBACKGROUND: Determining the maximum tolerated dose (MTD) remains the primary objective for the majority of dose-finding oncology trials. Whilst MTD determination often relies upon clinicians to identify dose-limiting toxicities (DLTs) experienced by patients during the trial, research suggests that clinicians may underreport patient's adverse events. Therefore, contemporary practice may be exposed to recommending intolerable doses to patients for further investigation in subsequent trials. There is increasing interest in patients self-assessing their own symptoms using patient-reported outcomes (PROs) in dose-finding trials. DESIGN: We present Utility-PRO-Continual Reassessment Method (U-PRO-CRM), a novel trial design which simultaneously uses clinician-rated and patient-rated DLTs (Clinician-DLTs and Patient-DLTs, respectively) to make dose (de-)escalation decisions and to recommend an MTD. U-PRO-CRM contains the published PRO-CRM as a special case and provides greater flexibility to trade-off the rate of Patient-DLTs and Clinician-DLTs to find an optimal dose. We present simulation results for U-PRO-CRM. RESULTS: For specified trade-offs between Clinician-DLT and Patient-DLT rate, U-PRO-CRM outperforms the PRO-CRM design by identifying the true MTD more often. In the special case where U-PRO-CRM generalises to PRO-CRM, U-PRO-CRM performs as well as its published counterpart. U-PRO-CRM minimises the number of patients overdosed whilst maintaining a similar proportion of patients allocated to the true MTD. CONCLUSIONS: By using a utility-based dose selection approach, U-PRO-CRM offers the flexibility to define a trade-off between the risk of patient-rated and clinician-rated DLTs for an optimal dose. Patient-centric dose-finding strategies, which integrate PROs, are poised to assume an ever more pivotal role in significantly advancing our understanding of treatment tolerability. This bears significant implications in shaping the future landscape of early-phase trials
Systemic biomarkers of immune response in locally-advanced human papillomavirus malignancies treated with radical chemoradiation
No full textHuman papillomavirus (HPV)-driven malignancies exhibit viral oncogenic proteins that act as tumour-specific antigens, making them suitable candidates for monitoring the adaptive immune response during treatment. Chemoradiation is the primary treatment modality for locally-advanced HPV-related malignancies, achieving high efficacy; however, approximately 25 to 30% of patients experience relapse within five years after treatment. It is increasingly recognized that chemoradiation influences the anti-cancer immune response, but the clinical relevance of these processes in the context of treatment response remains unclear. In this research endeavour, I investigate the pre-treatment tumour microenvironment and the dynamics of the systemic adaptive immune response in locally-advanced HPV-driven malignancies undergoing radical chemoradiation. The primary objective of this study is to identify potential biomarkers that can serve as reliable determinants for predicting treatment response. To achieve this comprehensive exploration, a multifaceted approach is needed, encompassing accurate collection, processing, sequencing protocols, and statistical methodologies. Thus, first I examined and optimized various protocols for sample collection, processing, and T-cell receptor (TCR) sequencing methodologies. These protocols will later be implemented in the translational clinical trials of this research. I developed and benchmarked a bioinformatic tool to facilitate population-wide immunogenic epitope discovery, with a specific focus on HPV-derived oncogenic proteins. Next, I investigated the TCR repertoire in a cohort of HPV-positive locally-advanced oropharyngeal, cervical, and anal carcinomas treated with chemoradiation, aiming to identify specific characteristics associated with treatment response. The understanding of systemic immune dynamics is further expanded in a cohort of locally-advanced head and neck carcinomas treated with chemoradiation through a multi-omic characterisation that integrates intra-tumoural and peripheral TCR sequencing, circulating HPV16 DNA analysis, and peripheral immune profiling. Lastly, the HPV genome status and tumour microenvironment are interrogated in a large cohort of locally-advanced head and neck cancers, providing valuable insights into the interplay betwee