Trophoblast Glycoprotein is Associated With a Favorable Outcome for Mesothelioma and a Target for Antibody Drug Conjugates

Our plain-English summary of Trophoblast Glycoprotein is Associated With a Favorable Outcome for Mesothelioma and a Target for Antibody Drug Conjugates, by L.M. Schunselaar, K. Monkhorst, V. van der Noort, et al (Journal of Thoracic Oncology, 2018).

The study

• Authors: L.M. Schunselaar, K. Monkhorst, V. van der Noort, R. Wijdeven, D. Peters, W. Zwart, J. Neefjes, P. Baas
• Journal: Journal of Thoracic Oncology
• Published: 2018;13(10):1577-1587
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: The prognosis for patients with mesothelioma is poor, which prompts the need for the development of better treatment options. Antibody drug conjugates (ADCs) are gaining interest as a therapeutic strategy in mesothelioma. Trophoblast glycoprotein (5T4) is an oncofetal protein overexpressed in mesothelioma with low expression in normal tissue and therefore a good candidate for ADC treatment. Here, we evaluated and manipulated 5T4 as a suitable antigen for ADC targeted therapy in patients with mesothelioma.

Methods: Expression of the 5T4 antigen is evaluated in (primary) mesothelioma cell lines and biopsy specimens, and correlated with clinical outcome. Internalization was assessed in 5T4 expressing cells. The cytotoxicity of three different 5T4-targeting ADCs was tested on (primary) mesothelioma cells.

Results: 5T4 was expressed in 10 of 12 (primary) cell lines. Most biopsy specimens stained positive for the 5T4 antigen, with marked differences in staining intensity and percentage of positive cells. High expression correlated with long progression-free survival. Both free antibody and ADCs targeting 5T4 were internalized and entered lysosomal compartments. Cytotoxicity experiments showed that cell lines with a high expression for 5T4 were sensitive to two of three ADCs. Lack of efficacy for the third ADC could be restored by neutralizing lysosomal compartments with chloroquine.

Conclusions: The 5T4 antigen is expressed in mesothelioma and 5T4-based ADCs are internalized in lysosomes. Two of three ADCs were capable of killing the mesothelioma cells; the third ADC required additional lysosomal neutralization for its effect. 5T4-based ADCs would be a selective strategy for the treatment of mesothelioma.

Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study examined a protein called trophoblast glycoprotein (5T4) in malignant pleural mesothelioma. It did not study asbestos exposure. 5T4 was found in 7 of 8 established mesothelioma cell lines and 3 of 4 grown from patients. The researchers studied 49 biopsy specimens from the Netherlands Cancer Institute. Among 42 patients assessed for progression-free survival, those with higher tumor 5T4 levels (H-score above 60) had a median of 12 months (95% confidence interval 4 to 18), against 5 months (4 to 8) with lower levels. Among 49 patients, median overall survival was 26.5 months (22.9 to 33) against 12 months (8.84 to 22.5). This was an association, not proof of cause. Three antibody drug conjugates (antibodies carrying a cell-killing toxin) were tested. Two killed all three high-5T4 lines tested. The third did not, but adding chloroquine restored its killing in H2810, the one high-5T4 line shown. One normal mesothelial line and two low- or medium-5T4 lines were insensitive to all three. The authors concluded that 5T4-targeting treatment could be promising for mesothelioma with high 5T4 expression.

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: Laboratory study of mesothelioma cell lines (protein expression, uptake into cells, and drug cell-killing tests), combined with an analysis of patient biopsy specimens and their survival
• Who was studied: Eight established malignant pleural mesothelioma (MPM) cell lines, four primary MPM cell lines and one normal mesothelial cell line (Met5A). Also 49 MPM biopsy specimens (34 epithelial, 8 mixed, 7 sarcomatoid) from patients at the Netherlands Cancer Institute, collected 2009 to 2015. Progression-free survival was determined for 42 patients and overall survival for 49.
• Exposure: Not asbestos. The study measured expression of the 5T4 protein. It also tested three 5T4-targeting antibody drug conjugates on cells (A1-mcMMAF, H8-mcMMAF and H8-vcMMAE), with and without chloroquine.
• Main results:
  • Cell lines: 7 of 8 established MPM cell lines and 3 of 4 primary cell lines stained positive for 5T4. The normal mesothelial cell line Met5A expressed 5T4 at only very low levels.
  • Normal tissue: 5T4 was not found in a tissue microarray of normal tissues (including intestine, liver, kidney, prostate and lung).
  • Cell uptake: the anti-5T4 antibody H8 was taken into high-5T4 cells. Uptake reached 80% to 90% after 12 hours in H2810 and VAMT cells, and 100% after 24 hours in the primary cell line PV130913.
  • Progression-free survival was determined for 42 patients and overall survival for 49 patients.
  • Progression-free survival in biopsy patients: median 12 months (95% CI 4 to 18 months) with high 5T4 expression (H-score above 60), versus 5 months (95% CI 4 to 8 months) with low expression.
  • Overall survival in biopsy patients: median 26.5 months (95% CI 22.9 to 33 months) with high 5T4 expression, versus 12 months (CI 8.84 to 22.5 months) with low expression.
  • In univariate analysis, high 5T4 expression was associated with longer progression-free survival (p = 0.006, hazard ratio 0.38, 95% CI 0.19 to 0.76).
  • In univariate analysis, high 5T4 expression was associated with longer overall survival (p = 0.011, hazard ratio 0.46, 95% CI 0.25 to 0.85).
  • The association with longer survival also held in multivariate analysis adjusting for age, sex, histologic subtype (epithelial versus nonepithelial) and, for overall survival only, disease control at 6 weeks.
  • Independent of 5T4, the nonepithelial subtype was associated with shorter progression-free and overall survival.
  • Drug tests on cells: all high-5T4 cell lines tested (H2810, PV130913 and PV180314) were sensitive to A1-mcMMAF and H8-mcMMAF, but not to H8-vcMMAE.
  • In the cell-survival tests, the normal mesothelial cell line Met5A was insensitive to all three drugs. So were the low-5T4 line H2052 and the medium-5T4 line H2731.
  • When chloroquine was added to neutralize the cells' lysosomes, mesothelioma cells treated with H8-vcMMAE were killed. The article shows the results of this test for one high-5T4 cell line, H2810.
• The authors' conclusion: The authors concluded that antibody drug conjugate treatment targeting 5T4 could be a promising new strategy for malignant pleural mesothelioma with high 5T4 expression. They described their study as a first proof-of-concept.
• Limitations the authors state:
  • Larger numbers of cell lines or primary tumor cultures are needed to find the 5T4 expression cut-off required for the drugs to work.
  • The effect of drug trapping in lysosomes needs study in systems closer to real conditions in the body.
  • Differences between cell lines and biopsy specimens make it hard to compare 5T4 expression between the two.
  • In the cell uptake test, the method for blocking the signal from antibody on the cell surface was incomplete, leaving a background signal.

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: Glycoprotein, Mesothelioma, Prognosis, Targeted Therapy, Biopsy, Progression-Free Survival.

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