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

Cancer Biol Ther. 2018 Jul 3;19(7):622-630. doi: 10.1080/15384047.2018.1449614. Epub 2018 Apr 25.

Abstract

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-γ 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 (∼3X 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-γ-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.

Keywords: ADCC; CA125; Fc-γ receptor; amatuximab; immune suppression; mesothelin; mesothelioma.

MeSH terms

  • Aged
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use
  • Antibody-Dependent Cell Cytotoxicity / immunology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • CA-125 Antigen / blood
  • CA-125 Antigen / genetics
  • CA-125 Antigen / immunology
  • CA-125 Antigen / metabolism*
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Clinical Trials, Phase II as Topic
  • Female
  • GPI-Linked Proteins / antagonists & inhibitors
  • GPI-Linked Proteins / immunology
  • GPI-Linked Proteins / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms / blood
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Membrane Proteins / blood
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mesothelin
  • Mesothelioma / blood
  • Mesothelioma / drug therapy*
  • Mesothelioma / mortality
  • Mesothelioma / pathology
  • Mesothelioma, Malignant
  • Middle Aged
  • Pemetrexed / pharmacology
  • Pemetrexed / therapeutic use
  • Pleural Neoplasms / blood
  • Pleural Neoplasms / drug therapy*
  • Pleural Neoplasms / mortality
  • Pleural Neoplasms / pathology
  • Progression-Free Survival
  • RNA, Small Interfering / metabolism
  • Receptors, IgG / immunology
  • Receptors, IgG / metabolism

Substances

  • Antibodies, Monoclonal
  • CA-125 Antigen
  • FCGR2A protein, human
  • GPI-Linked Proteins
  • MUC16 protein, human
  • Membrane Proteins
  • RNA, Small Interfering
  • Receptors, IgG
  • Pemetrexed
  • amatuximab
  • Mesothelin
  • Cisplatin