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

Our plain-English summary of CA125 suppresses amatuximab immune-effector function and elevated serum levels are associated with reduced clinical response in first line mesothelioma patients, by N.C. Nicolaides, C. Schweizer, E.B. Somers, et al (Cancer Biology & Therapy, 2018).

The study

• Authors: N.C. Nicolaides, C. Schweizer, E.B. Somers, W. Wang, S. Fernando, E.N. Ross, L. Grasso, R. Hassan, J.B. Kline
• Journal: Cancer Biology & Therapy
• Published: 2018;19(7):622-630
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This study combined a post hoc analysis of a single-arm Phase 2 trial with laboratory experiments. In the trial, patients with unresectable malignant pleural mesothelioma received the antibody drug amatuximab together with cisplatin and pemetrexed chemotherapy. The study did not examine asbestos exposure. Of 89 enrolled patients, 75 had measurable baseline blood levels of CA125, a protein shed by tumors. The authors identified 57 U/mL as the best dividing point. The 60 patients at or below 57 U/mL had better progression-free survival than the 15 patients above it (hazard ratio 0.43, p = 0.0062), and better overall survival (hazard ratio 0.40, p = 0.0022). Results were similar when only stage III/IV patients were analyzed. In laboratory tests, CA125 bound amatuximab and reduced its ability to direct immune cells against mesothelin-positive tumor cells. The authors concluded that baseline CA125 levels were associated with clinical outcome in these patients. They noted that the trial had no chemotherapy-only control arm. All authors except one were employees of Morphotek.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Post hoc subgroup analysis of a single-arm Phase 2 clinical trial, combined with in vitro laboratory (cell and molecular) experiments
• Who was studied: Patients with unresectable malignant pleural mesothelioma in the MORAb-009-003 Phase 2 trial. Of 89 enrolled, 75 had measurable baseline CA125 and were analyzed: 60 at or below 57 U/mL and 15 above 57 U/mL. Laboratory work used tumor cell lines including OVCAR3 (ovarian), A431 engineered to express mesothelin, and CHO-mesothelin cells.
• Exposure: No asbestos exposure was studied. The factor examined was baseline serum CA125 level, split at 57 U/mL, in patients treated with amatuximab (an antibody targeting mesothelin) plus cisplatin and pemetrexed.
• Main results:
  • Patients with baseline CA125 at or below 57 U/mL (N = 60) had improved progression-free survival (HR 0.43, p = 0.0062) and overall survival (HR 0.40, p = 0.0022) compared with patients above 57 U/mL (N = 15).
  • Restricted to stage III/IV patients only, those at or below 57 U/mL still had improved progression-free survival (HR 0.42, p = 0.0074) and overall survival (HR 0.38, p = 0.0016) compared with those above the threshold.
  • Overall response rate was 33% in the low-CA125 group vs 20% in the high-CA125 group (no p-value given).
  • Two other tumor markers, CA15-3 and CA19-9, showed no correlation with response.
  • Baseline CA125 levels did not correlate significantly with tumor size measured on CT scans.
  • In laboratory assays, soluble CA125 suppressed amatuximab-mediated ADCC (antibody-directed immune-cell killing) against mesothelin-positive tumor cell lines.
  • CA125 bound amatuximab, apparently in the (Fab')2 portion of the antibody rather than the Fc portion.
  • CA125 reduced amatuximab binding to the CD16a receptor by 50% (p = 0.0000009) and to CD32a by 29% (p less than 0.003). It did not reduce binding to CD64a (0%, p = 0.380).
• The authors' conclusion: The authors concluded that baseline CA125 levels were associated with clinical outcome in malignant pleural mesothelioma patients treated with amatuximab plus cisplatin and pemetrexed. They suggested that trials of antibody drugs bound by CA125 should consider stratifying patients by baseline CA125.
• Limitations the authors state:
  • The trial had no cisplatin/pemetrexed-only control arm.
  • The suggested CA125/amatuximab threshold effect needs testing in larger clinical studies.
  • The CA125 knockdown cell system was derived from ovarian cancer cells, not mesothelioma cells.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Monoclonal Antibody, Mesothelin, Unresectable, Cisplatin, Pemetrexed (Alimta), Overall Survival, Clinical Trial.

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• Safety and biodistribution of 111In-amatuximab in patients with mesothelin expressing cancers using single photon emission computed tomography-computed tomography (SPECT-CT) imaging — L. Lindenberg, A. Thomas, et al. (2015)
• Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection — A. Gupta, Z. Hussein, et al. (2016)
• Elevated Circulating Activin A Levels in Patients With Malignant Pleural Mesothelioma Are Related to Cancer Cachexia and Reduced Response to Platinum-based Chemotherapy — J. Paajanen, I. Ilonen, et al. (2020)
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• Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052) — M.E. O'Brien, R.M. Gaafar, et al. (2013)

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