Melero I.,University of Navarra |
Gaudernack G.,University of Oslo |
Gerritsen W.,mc Cancer Center Amsterdam |
Huber C.,Johannes Gutenberg University Mainz |
And 7 more authors.
Nature Reviews Clinical Oncology | Year: 2014
The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy. © 2014 Macmillan Publishers Limited.
Agency: GTR | Branch: STFC | Program: | Phase: Research Grant | Award Amount: 96.77K | Year: 2015
With this grant we will develop the first system for accurately validating organ dose estimates for patients receiving cancer therapy using radioactive materials which target their tumours, known as Molecular Radiotherapy (MRT). Currently simple water filled cylinders or spheres of varying sizes are used to represent patient organs when testing the accuracy of measurements of radiation dose delivered to tumours and critical organs in a patients body. These cylinders are used as a calibration to convert the number of gamma rays detected in a SPECT gamma-camera system to an activity inside a patients organ. Our current research has shown that this calibration method can actually result in organ dose estimates with systematic errors of up to 40%, preventing individualised patient treatments from being optimised. Consequently a significant number of patients do not currently receive the optimal therapy. By using realistic 3D printed models based on CT scans of patient organs we can accurately determine how well current commercial systems measure the dose to individual patient organs. This provides the first rigorous validation of these systems, a necessary requirement if the systems are to be used for all patient therapies. Our 3D printed models will also provide a much more accurate activity calibration, based on real organ geometries, for the SPECT scanner systems used to measure dose for MRT. Accurate MRT dose information is now considered very important in countries across Europe. Legislation now recommends accurate dosimetry for every patient receiving Molecular radiotherapy treatment. Our research will provide a new gold standard for assessing dosimetry systems used in clinical departments. This will highlight any weaknesses in current systems and in combination with our new realistic calibration factor measurements will allow the accuracy of dose measurements to be improved for all SPECT camera systems and MRT therapies. By establishing the accuracy of current dosimetry systems we will be able to provide a pathway to improve current commercial systems based on techniques from our recent research and future developments based on our 3D printed models. We are currently working with a leading provider of nuclear medicine workstation software who are supporting our work to validate their system. A rigorously validated commercial system has the potential to provide a significant improvement in the outcome of an estimated 201,00 MRT therapies performed annually in Europe.
Butts C.,Cross Cancer Institute |
Socinski M.A.,UPMC Cancer Pavilion |
Mitchell P.L.,Austin Hospital |
Thatcher N.,Christie Hospital NHS Trust |
And 18 more authors.
The Lancet Oncology | Year: 2014
Background: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. Methods: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. Findings: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5-29·2) with tecemotide versus 22·3 months (19·6-25·5) with placebo (adjusted HR 0·88, 0·75-1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6-36·8) compared with 20·6 months (17·4-23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64-0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months [95% CI 17·6-23·1] vs 24·6 months [18·8-33·0], respectively; adjusted HR 1·12, 0·87-1·44; p=0·38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. Interpretation: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Funding: Merck KGaA (Darmstadt, Germany). © 2014 Elsevier Ltd.
Samol J.,St Georges Hospital |
Ranson M.,Christie Hospital NHS Trust |
Scott E.,University of Leicester |
MacPherson E.,Astrazeneca |
And 3 more authors.
Investigational New Drugs | Year: 2012
Background: The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. Patients and methods Patients aged ≥18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m2/day×3 days or 1.0 mg/m2/day×3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan. Results:: Twentyone patients were enrolled and 19 received treatment. Doselimiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m2/day× 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting. Conclusion:s Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD. © Springer Science+Business Media, LLC 2011.
McDermott D.,Beth Israel Deaconess Medical Center |
Haanen J.,Netherlands Cancer Institute |
Chen T.-T.,Bristol Myers Squibb |
Lorigan P.,Christie Hospital NHS Trust |
O'Day S.,Los Angeles Skin Cancer Institute
Annals of Oncology | Year: 2013
Background: In a phase III trial (ClinicalTrials.gov registration ID: NCT00094653), ipilimumab significantly improved survival versus a vaccine control in pretreated patients with metastatic melanoma. Here, we characterize outcomes of those patients who survived >2 years. Methods: Patients were randomized (3: 1: 1) to receive ipilimumab 3 mg/kg + gp100 vaccine, ipilimumab 3 mg/kg + placebo, or gp100 vaccine alone. Baseline demographic data, duration of survival, responses, and safety among patients with >2 years' survival were analyzed. Results: Among 676 randomized patients, 474 and 259 patients had at least 2 or 3 years of potential follow-up, respectively, and were eligible for analysis. Among these, 94 (20%) and 42 (16%) survived >2 and >3 years, respectively. Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimumab alone and 19% (54 of 284) and 15% (24 of 156) with ipilimumab plus gp100. Safety among patients with >2 years' survival was comparable with the overall study population, with the onset of new ipilimumab-related toxic effect (all grades) reported in 6 of 78 (8%) patients. Conclusions: Ipilimumab results in survival of >2 years in one-fifth of pretreated patients with 2 years potential follow-up in a phase III trial. New onset, low-grade events starting after administration of the last dose were infrequent. Trial Registration ID: NCT00094653. © The Author 2013.
Shalet S.M.,Christie Hospital NHS Trust
Clinical Endocrinology | Year: 2010
Quantitatively, GH secretion exists as a continuum in states ranging from good health through to hypopituitarism. Currently, GH replacement is considered only for adults designated as being severely GH deficient (GHD). In clinical practice the gold standard, on which the biochemical diagnosis of severe GHD is based, centres on the presence of two or more additional anterior pituitary hormone deficits. Cohorts of adults with partial GHD (Growth Hormone Insufficiency [GHI]) have been reported with adverse body composition changes, dyslipidaemia, insulin resistance, altered cardiac performance and increased carotid intima-media thickness. The diagnosis of GHI in an individual patient, however, is extremely difficult because such patients rarely exhibit additional anterior pituitary hormone deficits, and the levels of GH-dependent proteins, including IGF-I, are normal in the majority. Currently, GH replacement therapy should only be considered in a patient characterized as GHI by dynamic GH testing in whom there is a plausible cause for hypopituitarism and in whom the IGF-I level is pathologically low. © 2010 Blackwell Publishing Ltd.
Thatcher N.,Christie Hospital NHS Trust |
Heighway J.,Cancer Communications and Consultancy Ltd
Oncologist | Year: 2010
Globally, lung cancer is the leading cause of cancerrelated mortality. Current chemotherapy combinations for the first-line treatment of advanced disease (stage IIIB with malignant pleural effusion/stage IV) and chemoradiotherapy regimens for the treatment of unresectable locally advanced disease (stage IIIA and IIIB without malignant pleural effusion) appear to have reached an efficacy plateau. The addition of new compounds including targeted agents to standard first-line cytotoxic doublets, administered concurrently and/or as maintenance therapy in patients who have not experienced disease progression after such treatment, has been shown to improve efficacy beyond this plateau in patients with advanced disease. However, to date, such approaches have been less successful in the treatment of patients with unresectable locally advanced stage III disease. The purpose of this review is to summarize the data from recent randomized phase III studies involving agents administered as maintenance or consolidation therapy in the treatment of unresectable stage III/IV non-small cell lung cancer (NSCLC).Apossible alternative approach to the use of cytotoxic or molecularly targeted agents in this setting is the administration of therapeutic anticancer vaccines, which are designed to stimulate a host immunological response against the tumor. Current data in relation to the potential of vaccine therapy for NSCLC are therefore also reviewed, with a particular focus on belagenpumatucel- L and L-BLP25 vaccines, which are currently undergoing phase III evaluation as maintenance therapies in patients with unresectable stage III/IV NSCLC who have tumor control following first-line therapy. © AlphaMed Press.
Peters S.,University of Lausanne |
Taron M.,University of Barcelona |
Bubendorf L.,University of Basel |
Blackhall F.,Christie Hospital NHS Trust |
Stahel R.,University of Zürich
Lung Cancer | Year: 2013
The recent approval of crizotinib for the treatment of anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC) in the US and other countries has provoked intense interest in ALK rearrangements as oncogenic drivers, and promises to revolutionise the way in which NSCLC is diagnosed and treated. Here, we review clinical data to date for the use of crizotinib to treat patients with advanced, ALK-positive NSCLC and consider issues surrounding the detection of ALK-positivity including the use of fluorescence in situ hybridisation and the other potential techniques available, and their suitability for ALK screening. We also discuss the emergence of resistance to crizotinib therapy and the range of other ALK inhibitors currently in development. © 2013 Elsevier Ireland Ltd.
Shalet S.M.,Christie Hospital NHS Trust
European journal of endocrinology / European Federation of Endocrine Societies | Year: 2013
In the UK, through the use of a forced economic model, endocrinologists are in the curious position of offering GH replacement to some patients with severe GH deficiency (GHD) but withholding it from other patients with even more severe GHD. This approach is counter-intuitive to endocrine practice in treating endocrine deficiency states. For all other endocrine deficiencies, one would opt for treating those with the most severe biochemical evidence of deficiency first. If this endocrine approach was applied to adult GH replacement in an era of rationing, one would start with the GHD patients with a pathologically low IGF1 level. Given that the prevalence of subnormal IGF1 levels in a GHD population is age-dependent, this would result in GH replacement being offered to more young adult onset (AO) GHD and childhood onset GHD adults, and less often to middle-aged and elderly AO GHD adults. This in itself has the added advantage that the skeletal benefits appear more real in the former cohort of patients.
Agency: GTR | Branch: MRC | Program: | Phase: Research Grant | Award Amount: 285.89K | Year: 2014
Radiotherapy is an important cancer treatment given to about 125,000 patients each year. It is typically delivered in daily doses (fractions) over a period of several weeks using multiple high energy X-ray (and now proton) beams. The beams are individually shaped for each patient and designed to overlap at the precise location of the target disease. The intention is to give maximum dose to the cancer cells while minimising dose to nearby healthy tissues. Usual practice is to plan the arrangement and shape of these treatment beams based on CT images taken before treatment begins. Ensuring that the patient and their tumour target are in the correct position for treatment on each day of their therapy is challenging. Small changes (more than a few millimetres) could invalidate the pre-treatment planning leading to the target receiving too low a dose of radiation (and hence reduced chance of cure) or healthy tissues receiving too high a dose of radiation (and hence increased chance of side effects). The use of cone-beam CT (CBCT) imaging within the treatment room to check patient position, pose, and anatomy just before the radiation beams are switched on has recently become widespread. However, changes in patient shape can be complex, making it difficult to calculate whether the resulting change in radiation dose received will be significant - that is, will it be necessary to alter the pre-planned treatment to take account of the change? Our aim is to simplify this decision process. We will develop a computerised method that uses a patients CBCT image to calculate changes from their prescribed and planned dose. Currently this is not possible because calculation of radiation dose requires accurate data on tissue density within the patient, in order to determine how X-rays (or protons) will interact with their anatomy. Unlike CT images, which are used to generate the initial treatment plan, CBCT images do not give accurate information on tissue density. This project will develop a method to correct the CBCT images so that the tissue density information that they contain can be used to directly compute delivered doses. This will be of significant benefit to radiotherapy patients since staff we be able to quickly check that the correct dose will be delivered, or if it is necessary to take action to avoid incorrect doses. Currently this process is very time consuming - tissue boundaries have to be manually drawn onto CBCT images and assumed density values assigned to each region. The technology we propose to develop will accelerate such assessments, estimated to be necessary for about one fifth of CBCT images. A further benefit is that our correction method not only restores accurate CBCT density values, but also markedly improves visual image quality. This makes images easier to interpret and more suitable for automatic analysis, with potential for further time savings. The project builds on our previous work, where we have developed a correction method that appears to be effective for pelvic or head and neck images. We have acquired a UK patent for this invention, ensuring that benefits and value to the NHS can be maximised. In this project we propose to extend our method for use in lung images. This site is challenging due to the large differences in tissue densities present (lung, soft-tissue, bone), and the inherent respiratory motion. We will additionally investigate the suitability of corrected CBCT images for the planning of proton radiotherapy, a looming challenge as we move towards the opening of the first high-energy proton therapy centres in the UK.