14 research outputs found
Lymphodepletion strategies to potentiate adoptive T-cell immunotherapy–what are we doing; where are we going?
No full textIntroduction: Adoptive immunotherapy of cancer has evolved from the use of ex vivo expanded lymphokine-activated killer cells and tumor-infiltrating lymphocytes to an increasing array of approaches involving genetically engineered T-cells. A pivotal advance in the enablement of these therapies has been the conditioning of patients with lymphodepleting chemotherapy. A broad range of lymphodepleting regimens has been employed in an effort to improve response rates, without any single consistent approach having emerged. Only a limited number of studies involving small numbers of patients has directly compared two or more regimens, making it challenging to infer which are the preferred agents and dosing schedules. This difficulty is compounded by the fact that both response rate and toxicity appear to be disease-, patient- and T-cell product specific. Expert Opinion: This article surveys clinical experience with lymphodepleting regimens that have been used in conjunction with adoptive T-cell immunotherapy, focussing in particular on studies where different approaches have been employed. Harnessing this limited and evolving clinical experience, we set out to provide potential insights into how an optimal balance may be achieved between efficacy and safety. Intermediate dose fludarabine-based regimens are emerging as an increasingly popular option in an attempt to achieve this goal, although further studies are required to provide definitive evidence.</p
The Helping Everyone Achieve Long Term Health Passport : exploring potential use of the HEALTH Passport in primary and secondary schools
Get PDFChronic disease is a significant burden on the global population. The Helping Everyone Achieve Long Term Health (HEALTH) Passport is a paper-based approach previously utilized to help adults modify clinical risk factors through lifestyle, which may be effective in improving the long-term health of school-age children. This study investigates the feasibility of in-school use by engaging trainee teachers in primary and secondary education. Two hundred and fifty six unique responses were collated to evaluate current teaching of the main health risk factors and HEALTH Passports specifically adapted for schools. Trainees attended workshops with pre- and post-questionnaires used to measure training efficacy and evaluate the Passports' suitability for in-school use. Narrative analysis of feedback was performed. Feedback received for both Passports was positive overall. Trainees highlighted the need for the Passports to be further age differentiated. Significantly increased confidence (P < 0.01) in knowledge of exercise, type 2 diabetes, weight and blood pressure was shown. Confidence in smoking, drugs and alcohol knowledge was reduced highlighting the requirement for further teacher training. The HEALTH Passport has potential as an intervention to improve health literacy in school-age children. Age adaptation is needed with references to weight measures removed. Emotional well-being should be focused on, and data management stringently assessed for child protection. [Abstract copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: [email protected].
Fertility preservation, its effectiveness and its impact on disease status in pre-menopausal women with breast cancer : a systematic review and meta-analysis
No full textPreservation of reproductive function is a key concern for many premenopausal women with breast cancer, given the known gonadotoxic effects of treatments. The present systematic review aimed to investigate the effectiveness and safety of fertility preservation strategies in pre-menopausal women with breast cancer. Primary research assessing fertility preservation strategies of any type was identified. Markers of preservation of fertility including return of menstrual function, clinical pregnancy rates and live birth rates were selected as main outcome measures. An additional analysis of safety data was also performed. Fertility preservation interventions were overall associated with higher fertility outcomes: with a pooled odds ratio 4.14 (95% CI 3.59-4.77) for any kind of fertility preservation intervention. This was seen both for return of menstruation and for clinical pregnancy rate, but not for live birth rates. Fertility preservation was associated with a reduced rate of disease recurrence (OR 0.63 (95% CI 0.49-0.81)), while there was no significant difference in disease free survival (OR 0.88 (95% CI 0.74-1.05)) or in overall survival (OR 0.9 (95% CI 0.74-1.10)) between the fertility preservation group and those who had not undergone fertility preservation. Fertility preservation is both effective in preserving reproductive function, and safe with regard to disease recurrence, disease free survival and overall survival in premenopausal women with breast cancer. [Abstract copyright: Copyright © 2023 Elsevier B.V. All rights reserved.
Generation of human parallel chimeric antigen receptor (pCAR) T cells to achieve synergistic T cell co-stimulation
Get PDFDual co-stimulation may be harnessed using parallel chimeric antigen receptors (pCARs) in which two distinct co-stimulatory units are adjacently localized on the plasma membrane. This protocol summarizes construct design, human T cell isolation, retroviral transduction, tissue culture expansion, and preclinical testing of pCAR T cells, exemplified by receptors that co-target avb6 integrin and ErbB dimers. For complete details on the use and execution of this protocol, please refer to Muliaditan et al. (2021)
Incidence and management of inflammatory arthritis in England before and during the COVID-19 pandemic: a population-level cohort study using OpenSAFELY
Get PDFBACKGROUND: The impact of the COVID-19 pandemic on the incidence and management of inflammatory arthritis is not understood. Routinely captured data in secure platforms, such as OpenSAFELY, offer unique opportunities to understand how care for patients with inflammatory arthritis was impacted upon by the pandemic. Our objective was to use OpenSAFELY to assess the effects of the pandemic on diagnostic incidence and care delivery for inflammatory arthritis in England and to replicate key metrics from the National Early Inflammatory Arthritis Audit. METHODS: In this population-level cohort study, we used primary care and hospital data for 17·7 million adults registered with general practices using TPP health record software, to explore the following outcomes between April 1, 2019, and March 31, 2022: (1) incidence of inflammatory arthritis diagnoses (rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and undifferentiated inflammatory arthritis) recorded in primary care; (2) time to first rheumatology assessment; (3) time to first prescription of a disease-modifying antirheumatic drug (DMARD) in primary care; and (4) choice of first DMARD. FINDINGS: Among 17 683 500 adults, there were 31 280 incident inflammatory arthritis diagnoses recorded between April 1, 2019, and March 31, 2022. The mean age of diagnosed patients was 55·4 years (SD 16·6), 18 615 (59·5%) were female, 12 665 (40·5%) were male, and 22 925 (88·3%) of 25 960 with available ethnicity data were White. New inflammatory arthritis diagnoses decreased by 20·3% in the year commencing April, 2020, relative to the preceding year (5·1 vs 6·4 diagnoses per 10 000 adults). The median time to first rheumatology assessment was shorter during the pandemic (18 days; IQR 8–35) than before (21 days; 9–41). The proportion of patients prescribed DMARDs in primary care was similar before and during the pandemic; however, during the pandemic, fewer people were prescribed methotrexate or leflunomide, and more were prescribed sulfasalazine or hydroxychloroquine. INTERPRETATION: Inflammatory arthritis diagnoses decreased markedly during the early phase of the pandemic. The impact on rheumatology assessment times and DMARD prescribing in primary care was less marked than might have been anticipated. This study demonstrates the feasibility of using routinely captured, near real-time data in the secure OpenSAFELY platform to benchmark care quality on a national scale, without the need for manual data collection. FUNDING: None
Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune-modifying therapies: a nationwide cohort study in the OpenSAFELY platform
Get PDFBACKGROUND: The risk of severe COVID-19 outcomes in people with immune-mediated inflammatory diseases and on immune-modifying drugs might not be fully mediated by comorbidities and might vary by factors such as ethnicity. We aimed to assess the risk of severe COVID-19 in adults with immune-mediated inflammatory diseases and in those on immune-modifying therapies. METHODS: We did a cohort study, using OpenSAFELY (an analytics platform for electronic health records) and TPP (a software provider for general practitioners), analysing routinely collected primary care data linked to hospital admission, death, and previously unavailable hospital prescription data. We included people aged 18 years or older on March 1, 2020, who were registered with TPP practices with at least 12 months of primary care records before March, 2020. We used Cox regression (adjusting for confounders and mediators) to estimate hazard ratios (HRs) comparing the risk of COVID-19-related death, critical care admission or death, and hospital admission (from March 1 to Sept 30, 2020) in people with immune-mediated inflammatory diseases compared with the general population, and in people with immune-mediated inflammatory diseases on targeted immune-modifying drugs (eg, biologics) compared with those on standard systemic treatment (eg, methotrexate). FINDINGS: We identified 17 672 065 adults; 1 163 438 adults (640 164 [55·0%] women and 523 274 [45·0%] men, and 827 457 [71·1%] of White ethnicity) had immune-mediated inflammatory diseases, and 16 508 627 people (8 215 020 [49·8%] women and 8 293 607 [50·2%] men, and 10 614 096 [64·3%] of White ethnicity) were included as the general population. Of 1 163 438 adults with immune-mediated inflammatory diseases, 19 119 (1·6%) received targeted immune-modifying therapy and 181 694 (15·6%) received standard systemic therapy. Compared with the general population, adults with immune-mediated inflammatory diseases had an increased risk of COVID-19-related death after adjusting for confounders (age, sex, deprivation, and smoking status; HR 1·23, 95% CI 1·20–1·27) and further adjusting for mediators (body-mass index [BMI], cardiovascular disease, diabetes, and current glucocorticoid use; 1·15, 1·11–1·18). Adults with immune-mediated inflammatory diseases also had an increased risk of COVID-19-related critical care admission or death (confounder-adjusted HR 1·24, 95% CI 1·21–1·28; mediator-adjusted 1·16, 1·12–1·19) and hospital admission (confounder-adjusted 1·32, 1·29–1·35; mediator-adjusted 1·20, 1·17–1·23). In post-hoc analyses, the risk of severe COVID-19 outcomes in people with immune-mediated inflammatory diseases was higher in non-White ethnic groups than in White ethnic groups (as it was in the general population). We saw no evidence of increased COVID-19-related death in adults on targeted, compared with those on standard systemic, therapy after adjusting for confounders (age, sex, deprivation, BMI, immune-mediated inflammatory diseases [bowel, joint, and skin], cardiovascular disease, cancer [excluding non-melanoma skin cancer], stroke, and diabetes (HR 1·03, 95% CI 0·80–1·33), and after additionally adjusting for current glucocorticoid use (1·01, 0·78–1·30). There was no evidence of increased COVID-19-related death in adults prescribed tumour necrosis factor inhibitors, interleukin (IL)-12/IL‑23 inhibitors, IL-17 inhibitors, IL-6 inhibitors, or Janus kinase inhibitors compared with those on standard systemic therapy. Rituximab was associated with increased COVID-19-related death (HR 1·68, 95% CI 1·11–2·56), with some attenuation after excluding people with haematological malignancies or organ transplants (1·54, 0·95–2·49). INTERPRETATION: COVID-19 deaths and hospital admissions were higher in people with immune-mediated inflammatory diseases. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune-modifying drugs for immune-mediated inflammatory diseases compared with those on standard systemic therapy. FUNDING: UK Medical Research Council, NIHR Biomedical Research Centre at King's College London and Guy's and St Thomas' NHS Foundation Trust, and Wellcome Trust
The development of a risk threshold to aid risk stratified approach to monitoring for haematological, hepatic and/or renal adverse drug reactions during established cs DMARD treatment for systemic autoimmune rheumatic diseases: a RAND/UCLA Appropriateness Method consensus study
Get PDFObjective To explore how appropriate different intervals between monitoring blood tests are considered in relation to the risk of clinically significant adverse drug reactions in adults prescribed csDMARDs for ≥1 year for systemic autoimmune rheumatic diseases (SARD). Method A RAND/UCLA Appropriateness Method consensus study was undertaken. Members of the BSR csDMARD guideline working group who manage adults with SARD participated. Experts rated the extent to which intervals between blood tests were appropriate using Likert-type scales with responses from 1 (totally inappropriate) to 9 (totally appropriate) for 9 scenarios with 5-year predicted risk of discontinuing treatment due to abnormal monitoring blood tests from 5% to 25%. Median score and the number that voted 1–3 (inappropriate), 4–6 (unsure), and 7–9 (appropriate) were calculated for every interval in each scenario. Scenarios for which agreement could not be reached in the first round were recirculated, enclosing individual round one response and the panel median score. Consensus that an interval was appropriate for a scenario was reached where the median panel score was ≥7 and up to 6 experts rated <7. The results were discussed with PPI members and experts. Results Twenty-one of the 27 invitees participated. They comprised 11 consultants/GPs, five specialist nurses, three pharmacists, and two rheumatology specialty trainees. Consensus was reached for all scenarios. Six- and three-monthly blood tests were agreed as appropriate when the predicted risk was ≤10% and >10% over 5-years respectively. Conclusion A threshold to aid risk-stratified monitoring during established csDMARD treatment was agreed for adults with SARD
The prescription and monitoring of conventional synthetic disease-modifying anti-rheumatic drugs: British Society for Rheumatology guideline scope
Get PDFLay Summary: What does this mean for patients? A revised guideline, produced by the British Society for Rheumatology (BSR), will provide up-to-date information about the safe prescribing and monitoring of the effects of non-biologic (or conventional synthetic) disease-modifying anti-rheumatic drugs (DMARDs). This guideline will be used by healthcare professionals, people living with autoimmune rheumatic diseases and other interested parties, such as patient groups and charities. DMARDs are a group of drugs prescribed to people with autoimmune rheumatic diseases. The main aims of these drugs are to control symptoms and reduce or prevent long-term progression of the disease. Biologic drugs and Janus kinase inhibitors—sometimes referred to as biologic DMARDs and targeted synthetic DMARDs, respectively—are excluded from this guideline. This article outlines the scope of the revised guideline for DMARD safety, which will be updated to include new information and is being extended to include children and young people. Guideline revisions will be undertaken by a working group of adult and paediatric and adolescent rheumatologists, other healthcare professionals and people living with autoimmune rheumatic disease. The guideline will be developed using the methods and processes outlined in the BSR document ‘Creating clinical guidelines: our protocol’
The prescription and monitoring of conventional synthetic disease-modifying anti-rheumatic drugs: British Society for Rheumatology guideline scope
No full textLay Summary: What does this mean for patients? A revised guideline, produced by the British Society for Rheumatology (BSR), will provide up-to-date information about the safe prescribing and monitoring of the effects of non-biologic (or conventional synthetic) disease-modifying anti-rheumatic drugs (DMARDs). This guideline will be used by healthcare professionals, people living with autoimmune rheumatic diseases and other interested parties, such as patient groups and charities. DMARDs are a group of drugs prescribed to people with autoimmune rheumatic diseases. The main aims of these drugs are to control symptoms and reduce or prevent long-term progression of the disease. Biologic drugs and Janus kinase inhibitors—sometimes referred to as biologic DMARDs and targeted synthetic DMARDs, respectively—are excluded from this guideline. This article outlines the scope of the revised guideline for DMARD safety, which will be updated to include new information and is being extended to include children and young people. Guideline revisions will be undertaken by a working group of adult and paediatric and adolescent rheumatologists, other healthcare professionals and people living with autoimmune rheumatic disease. The guideline will be developed using the methods and processes outlined in the BSR document ‘Creating clinical guidelines: our protocol’
Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors
Get PDFSecond generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3ζ) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling, and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity, and specificity, pCAR T cells consistently elicit superior anti-tumor activity compared with T cells that express traditional linear CARs
