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1.
BMC Cancer ; 24(1): 733, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38877461

RESUMEN

BACKGROUND: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel. METHODS: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a "significant IrAE" (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs. DISCUSSION: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment. TRIAL REGISTRATION: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Estudios Longitudinales , Inmunoterapia/métodos , Inmunoterapia/efectos adversos , Estudios de Cohortes , Monitorización Inmunológica/métodos , Melanoma/tratamiento farmacológico , Melanoma/inmunología
2.
Br J Haematol ; 196(4): 892-901, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34761389

RESUMEN

Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1-2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96-1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09-5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08-2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments.


Asunto(s)
Antígenos CD20/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , COVID-19/complicaciones , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/tratamiento farmacológico , Adulto , Antineoplásicos Inmunológicos/efectos adversos , COVID-19/etiología , COVID-19/inmunología , Femenino , Neoplasias Hematológicas/inmunología , Humanos , Leucemia/complicaciones , Leucemia/tratamiento farmacológico , Leucemia/inmunología , Masculino , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Estudios Prospectivos , Factores de Riesgo
3.
Radiother Oncol ; 189: 109940, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37813311

RESUMEN

Significant variation in treatment centre setup and radiotherapy practice for thymic epithelial tumours (TET) was identified through a comprehensive survey of current UK Clinical (Radiation) Oncology practice. Multi-centre collaboration and wider TET specific multidisciplinary team meetings are needed and will be essential for developing expertise in TET radiotherapy.


Asunto(s)
Neoplasias Glandulares y Epiteliales , Oncología por Radiación , Neoplasias del Timo , Humanos , Neoplasias del Timo/radioterapia , Neoplasias del Timo/patología , Neoplasias Glandulares y Epiteliales/radioterapia , Reino Unido
4.
Front Immunol ; 14: 1122430, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36776862

RESUMEN

Checkpoint inhibitors (CPIs) are monoclonal antibodies which, by disrupting interactions of immune checkpoint molecules with their ligands, block regulatory immune signals otherwise exploited by cancers. Despite revolutionary clinical benefits, CPI use is associated with an array of immune-related adverse events (irAEs) that mirror spontaneous autoreactivity. Severe irAEs necessitate pausing or stopping of CPI therapy and use of corticosteroids and/or other immunomodulatory interventions. Despite increasingly widespread CPI use, irAE pathobiology remains poorly understood; its elucidation may point to targeted mitigation strategies and uncover predictive biomarkers for irAE onset in patients, whilst casting new light on mechanisms of spontaneous immune-mediated disease. This review focuses on common CPI-induced irAEs of the gut, skin and synovial joints, and how these compare to immune-mediated diseases such as ulcerative colitis, vitiligo and inflammatory arthritis. We review current understanding of the immunological changes reported following CPI therapy at the level of peripheral blood and tissue. Many studies highlight dysregulation of cytokines in irAE-affected tissue, particularly IFNγ and TNF. IrAE-affected tissues are also predominantly infiltrated by T-cells, with low B-cell infiltration. Whilst there is variability between studies, patients treated with anti-programmed cell death-1 (PD-1)/PDL-1 therapies seem to exhibit CD8+ T-cell dominance, with CD4+ T-cells dominating in those treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy. Interestingly, CD8+CXCR3+ T-cells have been reported to be elevated in gastrointestinal, dermatological and musculoskeletal -irAE affected tissues. These findings may highlight potential opportunities for therapeutic development or re-deployment of existing therapies to prevent and/or improve the outcome of irAEs.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Enfermedades del Sistema Inmune , Neoplasias , Humanos , Anticuerpos Monoclonales/efectos adversos , Enfermedades del Sistema Inmune/etiología , Inmunoterapia/efectos adversos , Piel , Inhibidores de Puntos de Control Inmunológico/efectos adversos
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