RESUMEN
BACKGROUND: The T cell bispecific antibody cibisatamab (CEA-TCB) binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells, which triggers T cell killing of cancer cell lines expressing moderate to high levels of CEA at the cell surface. Patient derived colorectal cancer organoids (PDOs) may more accurately represent patient tumors than established cell lines which potentially enables more detailed insights into mechanisms of cibisatamab resistance and sensitivity. METHODS: We established PDOs from multidrug-resistant metastatic CRCs. CEA expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of PDOs and allogeneic CD8 T cells. RESULTS: PDOs could be categorized into 3 groups based on CEA cell-surface expression: CEAhi (n = 3), CEAlo (n = 1) and CEAmixed PDOs (n = 4), that stably maintained populations of CEAhi and CEAlo cells, which has not previously been described in CRC cell lines. CEAhi PDOs were sensitive whereas CEAlo PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEAlo cells maintain cancer cell growth. Culture of FACS-sorted CEAhi and CEAlo cells from PDOs with mixed CEA expression demonstrated high plasticity of CEA expression, contributing to resistance acquisition through CEA antigen loss. RNA-sequencing revealed increased WNT/ß-catenin pathway activity in CEAlo cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/ß-catenin pathway. CONCLUSIONS: Based on these preclinical findings, heterogeneity and plasticity of CEA expression appear to confer low cibisatamab sensitivity in PDOs, supporting further clinical evaluation of their predictive effect in CRC. Pharmacological inhibition of the WNT/ß-catenin pathway may be a rational combination to sensitize CRCs to cibisatamab. Our novel PDO and T cell co-culture immunotherapy models enable pre-clinical discovery of candidate biomarkers and combination therapies that may inform and accelerate the development of immuno-oncology agents in the clinic.
Asunto(s)
Anticuerpos Biespecíficos/farmacología , Antineoplásicos Inmunológicos/farmacología , Antígeno Carcinoembrionario/genética , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos , Técnicas de Cocultivo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Ensayos de Selección de Medicamentos Antitumorales , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Humanos , Técnicas de Cultivo de TejidosRESUMEN
The slow epidemic of liver disease in the UK over the past 30 years is a result of increased consumption of strong cheap alcohol. When we examined alcohol consumption in 404 subjects with a range of liver disease, we confirmed that patients with alcohol-related cirrhosis drank huge amounts of cheap alcohol, with a mean weekly consumption of 146 units in men and 142 in women at a median price of 33p/unit compared with £1.10 for low-risk drinkers. For the patients in our study, the impact of a minimum unit price of 50p/unit on spending on alcohol would be 200 times higher for patients with liver disease who were drinking at harmful levels than for low-risk drinkers. As a health policy, a minimum unit price for alcohol is exquisitely targeted at the heaviest drinkers, for whom the impact of alcohol-related illness is most devastating.
Asunto(s)
Bebidas Alcohólicas/economía , Hepatopatías Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/epidemiología , Comercio/estadística & datos numéricos , Femenino , Humanos , Cirrosis Hepática Alcohólica/epidemiología , Masculino , Reino Unido/epidemiologíaRESUMEN
Lemierre's disease is characterized by sepsis, often with an oropharyngeal source, secondary septic emboli and internal jugular vein thrombosis (Lancet 1:701-3, 1936. Clin Microbiol Rev 20(4):622-59, 2007). Septic emboli affecting many bodily sites have been reported, including the lungs, joints, bones, and brain. The case report describes an unusual case of Lemierre's disease in a 64 year old gentleman causing profound sepsis, acute kidney injury, bilateral iliopsoas abscesses and a right hand abscess. To our knowledge, this is the first reported case of Lemierre's disease in the context of bilateral psoas abscesses, and highlights the ambiguity surrounding the definition of Lemierre's disease. The clinical literature review highlights the difficulty in definitively diagnosing the condition and offers some suggestions for recognising and refining the diagnostic criterion of Lemierre's.