CA125 suppresses amatuximab immune-effector function and elevated serum levels are associated with reduced clinical response in first line mesothelioma patients.

Nicolaides, Nicholas C; Schweizer, Charles; Somers, Elizabeth B; Wang, Wenquan; Fernando, Shawn; Ross, Erin N; Grasso, Luigi; Hassan, Raffit; Kline, J Bradford

Nicolaides, Nicholas C; Schweizer, Charles; Somers, Elizabeth B; Wang, Wenquan; Fernando, Shawn; Ross, Erin N; Grasso, Luigi; Hassan, Raffit; Kline, J Bradford.

Afiliación

Nicolaides NC; a Morphotek Inc. , Exton , PA , USA.
Schweizer C; a Morphotek Inc. , Exton , PA , USA.
Somers EB; a Morphotek Inc. , Exton , PA , USA.
Wang W; a Morphotek Inc. , Exton , PA , USA.
Fernando S; a Morphotek Inc. , Exton , PA , USA.
Ross EN; a Morphotek Inc. , Exton , PA , USA.
Grasso L; a Morphotek Inc. , Exton , PA , USA.
Hassan R; b Thoracic and GI Oncology Branch , Head, Thoracic and Solid Tumor Immunotherapy Section, National Cancer Institute , Bethesda , Maryland , USA.
Kline JB; a Morphotek Inc. , Exton , PA , USA.

Cancer Biol Ther ; 19(7): 622-630, 2018 07 03.

Article en En | MEDLINE | ID: mdl-29652548

RESUMEN

The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-Î³ activating receptors on immune-effector cells. Amatuximab is a mAb targeting mesothelin whose mechanism of action utilizes in part antibody-dependent cellular cytotoxicity (ADCC). It is being tested for its therapeutic activity in patients with mesothelioma in combination with first line standard-of-care. To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. Analysis found patients with baseline CA125 levels no greater than 57 U/m (â¼3X the upper limit of normal) had a 2 month improvement in progression free survival (HR = 0.43, p = 0.0062) and a 7 month improvement in overall survival (HR = 0.40, p = 0.0022) as compared to those with CA125 above 57 U/mL. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-Î³-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125.

Asunto(s)

Anticuerpos Monoclonales/farmacología; Protocolos de Quimioterapia Combinada Antineoplásica/farmacología; Antígeno Ca-125/metabolismo; Neoplasias Pulmonares/tratamiento farmacológico; Proteínas de la Membrana/metabolismo; Mesotelioma/tratamiento farmacológico; Neoplasias Pleurales/tratamiento farmacológico; Anciano; Anticuerpos Monoclonales/uso terapéutico; Citotoxicidad Celular Dependiente de Anticuerpos/inmunología; Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico; Antígeno Ca-125/sangre; Antígeno Ca-125/genética; Antígeno Ca-125/inmunología; Línea Celular Tumoral; Cisplatino/farmacología; Cisplatino/uso terapéutico; Ensayos Clínicos Fase II como Asunto; Femenino; Proteínas Ligadas a GPI/antagonistas & inhibidores; Proteínas Ligadas a GPI/inmunología; Proteínas Ligadas a GPI/metabolismo; Técnicas de Silenciamiento del Gen; Humanos; Neoplasias Pulmonares/sangre; Neoplasias Pulmonares/mortalidad; Neoplasias Pulmonares/patología; Masculino; Proteínas de la Membrana/sangre; Proteínas de la Membrana/genética; Proteínas de la Membrana/inmunología; Mesotelina; Mesotelioma/sangre; Mesotelioma/mortalidad; Mesotelioma/patología; Mesotelioma Maligno; Persona de Mediana Edad; Pemetrexed/farmacología; Pemetrexed/uso terapéutico; Neoplasias Pleurales/sangre; Neoplasias Pleurales/mortalidad; Neoplasias Pleurales/patología; Supervivencia sin Progresión; ARN Interferente Pequeño/metabolismo; Receptores de IgG/inmunología; Receptores de IgG/metabolismo

Palabras clave

ADCC; CA125; Fc-Î³ receptor; amatuximab; immune suppression; mesothelin; mesothelioma

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pleurales / Protocolos de Quimioterapia Combinada Antineoplásica / Antígeno Ca-125 / Neoplasias Pulmonares / Proteínas de la Membrana / Mesotelioma / Anticuerpos Monoclonales Tipo de estudio: Risk_factors_studies Idioma: En Revista: Cancer Biol Ther Asunto de la revista: NEOPLASIAS / TERAPEUTICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google