Publications by authors named "Peter E Hall"

13 Publications

  • Page 1 of 1

Emerging drugs for the treatment of triple-negative breast cancer: a focus on phase II immunotherapy trials.

Expert Opin Emerg Drugs 2021 Jun 19;26(2):131-147. Epub 2021 Apr 19.

Dept. Of Medical Oncology, Barts Health NHS Trust, London, UK.

: Triple-negative breast cancer accounts for 10-20% of invasive breast cancers and is characterized by an aggressive phenotype and poor outcomes in the early and advanced settings compared to other breast cancer subtypes. Chemotherapy continues to be the mainstay of treatment, but recent advances have demonstrated the benefit of adding immune checkpoint inhibitors (ICIs) to chemotherapy regimens for patients with both early and advanced TNBC, particularly if PD-L1-positive. Despite these results, further improvements are needed.: This review covers immunotherapy drugs which have recently completed, involved in ongoing or due to start phase II trials. This includes approaches to augment the response to existing ICIs, next-generation ICIs, combination treatments with targeted agents and drugs that target the tumor microenvironment. Potential development issues are also discussed.: The field of immunotherapy is developing rapidly and holds great promise for patients with TNBC. Promising avenues of research currently in phase II trials include targeting multiple immune checkpoints simultaneously and the addition of phosphatidylinositol 3-kinase (PI3K)/AKT inhibitors to ICI/chemotherapy regimens. A better understanding of the immunosuppressive role played by the tumor microenvironment has also been important. However, challenges remain, particularly regarding the need for more effective predictive biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14728214.2021.1916468DOI Listing
June 2021

Phase II Study of Arginine Deprivation Therapy With Pegargiminase in Patients With Relapsed Sensitive or Refractory Small-cell Lung Cancer.

Clin Lung Cancer 2020 11 30;21(6):527-533. Epub 2020 Jul 30.

Department of Medical Oncology, Barts Health NHS Trust, London, United Kingdom; Centre for Molecular Oncology, Queen Mary University of London, London, United Kingdom. Electronic address:

Background: Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with argininosuccinate synthetase 1 (ASS1)-deficient small-cell lung cancer (SCLC).

Patients And Methods: Patients were enrolled into either a 'sensitive' disease cohort (≥ 90 days response to first-line chemotherapy) or a 'refractory' disease cohort (progression while on chemotherapy or < 90 days afterwards or ≥ third-line treatment). Patients received weekly intramuscular pegargiminase, 320 IU/m (36.8 mg/m), until unacceptable toxicity or disease progression. The primary endpoint was tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with secondary endpoints including tolerability, pharmacodynamics, and immunogenicity.

Results: Between January 2011 and January 2014, 22 patients were enrolled: 9 in the sensitive disease cohort and 13 in the refractory disease cohort. At a pre-planned interim analysis, the best overall response observed was stable disease in 2 patients in each cohort (18.2%). Owing to the lack of response and slow accrual in the sensitive disease cohort, the study was terminated early. Pegargiminase treatment was well-tolerated with no unexpected adverse events or discontinuations.

Conclusion: Although pegargiminase monotherapy in SCLC failed to meet its primary endpoint of RECIST-confirmed responses, more recent molecular stratification, including MYC status, may provide new opportunities moving forward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2020.07.012DOI Listing
November 2020

A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma.

Clin Cancer Res 2019 05 22;25(9):2708-2716. Epub 2019 Feb 22.

Department of Oncology, Barts Health NHS Trust, London, United Kingdom.

Purpose: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase () and/or argininosuccinate lyase (). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed.

Patients And Methods: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m intramuscularly plus pemetrexed 500 mg/m and cisplatin 75 mg/m intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy.

Results: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7).

Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-3729DOI Listing
May 2019

Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy.

Eur Urol Focus 2020 09 6;6(5):999-1005. Epub 2019 Feb 6.

Barts Cancer Institute, CRUK Experimental Cancer Medicine Centre, London, UK; Department of Oncology, Royal Free NHS Foundation Trust, London, UK. Electronic address:

Background: Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH).

Objective: To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC).

Design, Setting, And Participants: A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions.

Intervention: The phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition.

Outcome Measurements And Statistical Analysis: RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria.

Results And Limitations: In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39-2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43-3.14; p<0.001). Limitations include retrospective study design.

Conclusions: RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required.

Patient Summary: We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euf.2019.01.010DOI Listing
September 2020

Rationale for targeting the ErbB family of receptors in patients with advanced squamous cell carcinoma of the lung.

Future Oncol 2015 18;11(15):2175-91. Epub 2015 May 18.

Royal Marsden Hospital, London, UK.

Squamous cell carcinoma (SCC) of the lung represents around 30% of all non-small-cell lung cancers. Treatment options for nonsquamous histology have increased in recent years following the development of pemetrexed chemotherapy and the identification of activating EGFR mutations and ALK rearrangements as targets for effective noncytotoxic agents. By contrast, until recently the development of new therapies for SCC has lagged behind. However, the identification of important genetic events driving SCC, including a greater understanding of the role of the ErbB receptor family in SCC pathogenesis, as well as recent immunotherapy advances, have led to new treatment options for SCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon.15.110DOI Listing
April 2016

Lesson of the month 1: A rash decision.

Clin Med (Lond) 2015 Apr;15(2):206-7

Kingston Hospital NHS Foundation Trust, Kingston upon Thames, UK.

Cellulitis is a common condition and several mimics exist which should be considered in patients who fail to respond to antibiotics. We describe the case of a patient with anaplastic large cell lymphoma masquerading as a lower leg cellulitis. The patient had failed to respond to intravenous antibiotics and a skin biopsy confirmed her diagnosis. She received radical radiotherapy to the lower leg but later developed shortness of breath and was identified to have pulmonary infiltration of the lymphoma. She died shortly afterwards from lobar pneumonia. This case highlights the importance of regularly reassessing patients with suspected cellulitis and considering alternative diagnoses in cases that fail to respond to treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7861/clinmedicine.15-2-206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4953745PMC
April 2015

Laminin alpha 2 enables glioblastoma stem cell growth.

Ann Neurol 2012 Nov;72(5):766-78

Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Objective: Glioblastomas (GBMs) are lethal cancers that display cellular hierarchies parallel to normal brain. At the apex are GBM stem cells (GSCs), which are relatively resistant to conventional therapy. Interactions with the adjacent perivascular niche are an important driver of malignancy and self-renewal in GSCs. Extracellular matrix (ECM) cues instruct neural stem/progenitor cell-niche interactions, and the objective of our study was to elucidate its composition and contribution to GSC maintenance in the perivascular niche.

Methods: We interrogated human tumor tissue for immunofluorescence analysis and derived GSCs from tumor tissues for functional studies. Bioinformatics analyses were conducted by mining publicly available databases.

Results: We find that laminin ECM proteins are localized to the perivascular GBM niche and inform negative patient prognosis. To identify the source of laminins, we characterized cellular elements within the niche and found that laminin α chains were expressed by nonstem tumor cells and tumor-associated endothelial cells (ECs). RNA interference targeting laminin α2 inhibited GSC growth and self-renewal. In co-culture studies of GSCs and ECs, laminin α2 knockdown in ECs resulted in decreased tumor growth.

Interpretation: Our studies highlight the contribution of nonstem tumor cell-derived laminin juxtracrine signaling. As laminin α2 has recently been identified as a molecular marker of aggressive ependymoma, we propose that the brain vascular ECM promotes tumor malignancy through maintenance of the GSC compartment, providing not only a molecular fingerprint but also a possible therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.23674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615417PMC
November 2012

Single dose oral lornoxicam for acute postoperative pain in adults.

Cochrane Database Syst Rev 2009 Oct 7(4):CD007441. Epub 2009 Oct 7.

Keble College, University of Oxford, Parks Road, Oxford, Oxfordshire, UK, OX1 3PG.

Background: Lornoxicam is one of the oxicam class of non-steroidal anti-inflammatory drugs (NSAIDs), producing analgesic and antipyretic effects in part through the non-selective inhibition of cyclo-oxygenase-1 and -2. It is prescribed for osteoarthritis, rheumatoid arthritis, acute lumbar-sciatica conditions and for postoperative pain management. Lornoxicam is available in 31 countries in Europe, the Middle East, Far East and South America, and is becoming more widely available.

Objectives: To assess the efficacy, the time to onset of analgesia, the time to use of rescue medication and any associated adverse events of single dose oral lornoxicam in acute postoperative pain.

Search Strategy: We searched CENTRAL, MEDLINE, EMBASE and PubMed to June 2009.

Selection Criteria: Single oral dose, randomised, double-blind, placebo-controlled trials of lornoxicam for relief of established moderate to severe postoperative pain in adults.

Data Collection And Analysis: Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief over 6 hours (TOTPAR 6) was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals (CIs), the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected.

Main Results: Three studies, with 628 participants, met the inclusion criteria; 434 participants were treated with various doses (2 mg to 32 mg) of lornoxicam, 118 with placebo, and 76 with other active therapies. All the participants had pain following third molar extraction, and study duration was 8 to 24 hours. The NNT for at least 50% pain relief over 6 hours after a single dose of lornoxicam 8 mg was 2.9 (2.3 to 4.0). There were insufficient data to analyse other doses or use of rescue medication. No serious adverse events or withdrawals were reported by any of the studies.

Authors' Conclusions: Oral lornoxicam is effective at treating moderate to severe acute postoperative pain, based on limited data. Adverse events did not differ significantly from placebo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD007441.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485324PMC
October 2009

beta1 integrin maintains integrity of the embryonic neocortical stem cell niche.

PLoS Biol 2009 Aug 18;7(8):e1000176. Epub 2009 Aug 18.

Center for Neuroscience, Children's National Medical Center, Washington, D.C., United States of America.

During embryogenesis, the neural stem cells (NSC) of the developing cerebral cortex are located in the ventricular zone (VZ) lining the cerebral ventricles. They exhibit apical and basal processes that contact the ventricular surface and the pial basement membrane, respectively. This unique architecture is important for VZ physical integrity and fate determination of NSC daughter cells. In addition, the shorter apical process is critical for interkinetic nuclear migration (INM), which enables VZ cell mitoses at the ventricular surface. Despite their importance, the mechanisms required for NSC adhesion to the ventricle are poorly understood. We have shown previously that one class of candidate adhesion molecules, laminins, are present in the ventricular region and that their integrin receptors are expressed by NSC. However, prior studies only demonstrate a role for their interaction in the attachment of the basal process to the overlying pial basement membrane. Here we use antibody-blocking and genetic experiments to reveal an additional and novel requirement for laminin/integrin interactions in apical process adhesion and NSC regulation. Transient abrogation of integrin binding and signalling using blocking antibodies to specifically target the ventricular region in utero results in abnormal INM and alterations in the orientation of NSC divisions. We found that these defects were also observed in laminin alpha2 deficient mice. More detailed analyses using a multidisciplinary approach to analyse stem cell behaviour by expression of fluorescent transgenes and multiphoton time-lapse imaging revealed that the transient embryonic disruption of laminin/integrin signalling at the VZ surface resulted in apical process detachment from the ventricular surface, dystrophic radial glia fibers, and substantial layering defects in the postnatal neocortex. Collectively, these data reveal novel roles for the laminin/integrin interaction in anchoring embryonic NSCs to the ventricular surface and maintaining the physical integrity of the neocortical niche, with even transient perturbations resulting in long-lasting cortical defects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pbio.1000176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720642PMC
August 2009

Laminin enhances the growth of human neural stem cells in defined culture media.

BMC Neurosci 2008 Jul 23;9:71. Epub 2008 Jul 23.

Department of Pathology, University of Cambridge, Cambridge, UK.

Background: Human neural stem cells (hNSC) have the potential to provide novel cell-based therapies for neurodegenerative conditions such as multiple sclerosis and Parkinson's disease. In order to realise this goal, protocols need to be developed that allow for large quantities of hNSC to be cultured efficiently. As such, it is important to identify factors which enhance the growth of hNSC. In vivo, stem cells reside in distinct microenvironments or niches that are responsible for the maintenance of stem cell populations. A common feature of niches is the presence of the extracellular matrix molecule, laminin. Therefore, this study investigated the effect of exogenous laminin on hNSC growth.

Results: To measure hNSC growth, we established culture conditions using B27-supplemented medium that enable neurospheres to grow from human neural cells plated at clonal densities. Limiting dilution assays confirmed that neurospheres were derived from single cells at these densities. Laminin was found to increase hNSC numbers as measured by this neurosphere formation. The effect of laminin was to augment the proliferation/survival of the hNSC, rather than promoting the undifferentiated state. In agreement, apoptosis was reduced in dissociated neurospheres by laminin in an integrin beta1-dependent manner.

Conclusion: The addition of laminin to the culture medium enhances the growth of hNSC, and may therefore aid their large-scale production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2202-9-71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2496909PMC
July 2008

A study of the capability of manufacturers of generic hormonal contraceptives in lower- and middle-income countries.

Contraception 2007 Apr 16;75(4):311-7. Epub 2007 Jan 16.

Concept Foundation, Thailand Science Park, Pathumthani 12120, Thailand.

Purpose: Studies were undertaken to assess the capability, competence and capacity of manufacturers of oral and injectable hormonal contraceptives in lower- and middle-income countries.

Methods: A qualitative study on 41 companies, which comprised in-depth interviews and facility observations, was undertaken. Also an in-depth quantitative study of 14 companies was undertaken, of which 3 have not been included in the first study. Following review of a questionnaire and other documentation, a visit was undertaken to each factory to assess staff competence, manufacturing facilities, manufacturing processes, quality management, worker safety and environmental protection.

Results: Of the 44 companies from 15 countries, less than 30% would meet the current Good Manufacturing Practice requirements of the World Health Organization (WHO), the Pharmaceutical Inspection Cooperation Scheme or any stringent regulatory authority; a further 20% could comply with investment and improvements in quality management. Few companies are able to develop adequate registration dossiers.

Conclusion: There is a limited number of companies that are capable of manufacturing high-quality generic products and which can provide a complete registration dossier for use outside their home markets. It is essential that, in the future, procurement agencies only use suppliers that are prequalified by WHO for the procurement of hormonal contraceptives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.contraception.2006.11.008DOI Listing
April 2007

Integrins are markers of human neural stem cells.

Stem Cells 2006 Sep 11;24(9):2078-84. Epub 2006 May 11.

Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom.

The identification of markers for the isolation of human neural stem cells (hNSCs) is essential for studies of their biology and therapeutic applications. This study investigated expression of the integrin receptor family by hNSCs as potential markers. Selection of alpha6(hi) or beta1(hi) cells by fluorescence-activated cell sorting led to an enrichment of human neural precursors, as shown by both neurosphere forming assays and increased expression of prominin-1, sox2, sox3, nestin, bmi1, and musashi1 in the beta1(hi) population. Cells expressing high levels of beta1 integrin also expressed prominin-1 (CD133), a marker previously used to isolate hNSCs, and selection using integrin beta1(hi) cells or prominin-1(hi) cells was found to be equally effective at enriching for hNSCs from neurospheres. Therefore, integrin subunits alpha6 and beta1 are highly expressed by human neural precursors and represent convenient markers for their prospective isolation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1634/stemcells.2005-0595DOI Listing
September 2006

Results of phacoemulsification in eyes with preexisting glaucoma filters.

J Cataract Refract Surg 2003 Jun;29(6):1093-6

Ophthalmic Consultants of Boston, Center for Eye Research and Education, Boston, Massachusetts 02114, USA.

Purpose: To evaluate the intraocular pressure (IOP), best corrected visual acuity (BCVA), and glaucoma medication requirements in patients having phacoemulsification after preexisting glaucoma filters.

Setting: Ophthalmic Consultants of Boston, Boston, Massachusetts, USA.

Methods: A retrospective analysis of 58 eyes that had temporal phacoemulsification via a clear corneal (32 eyes) or a scleral tunnel (26 eyes) approach after filtration surgery was performed with a minimum follow-up of 12 months. Two-tailed homoscedastic t tests were used for statistical analysis.

Results: The mean preoperative IOP in all eyes was 11.8 mm Hg +/- 4.2 (SD), and the mean final postoperative IOP was 13.7 +/- 4.6 mm Hg (P<.022). The mean preoperative logMAR equivalent BCVA was 0.8 +/- 0.4, which improved to a mean of 0.4 +/- 0.4 postoperatively (P<.0000002). There was no statistically significant change in glaucoma medication requirements postoperatively. The differences in IOP, BCVA, and postoperative glaucoma medication requirements were not statistically significant between the clear corneal group and the scleral tunnel group or between patients who received mitomycin at the time of filtration surgery and those who did not. There were no intraoperative complications; 1 patient required additional glaucoma surgery.

Conclusion: Clear corneal or scleral tunnel phacoemulsification in the setting of a preexisting glaucoma filter was associated with improved BCVA, a small but statistically significant increase in IOP, and stability in the number of glaucoma medicines required for IOP control over a minimum follow-up of 1 year.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0886-3350(03)00133-0DOI Listing
June 2003
-->