Enhanced efficacy of mesothelin-targeted immunotoxin LMB-100 and anti-PD-1 antibody in patients with mesothelioma and mouse tumor models.

Abstract

LMB-100 is an immunotoxin targeting the cell surface protein mesothelin, which is highly expressed in many cancers including mesothelioma. Having observed that patients receiving pembrolizumab off protocol after LMB-100 treatment had increased tumor responses; we characterized these responses and developed animal models to study whether LMB-100 made tumors more responsive to antibodies blocking programmed cell death protein 1 (PD-1). The overall objective tumor response in the 10 patients who received PD-1 inhibitor (pembrolizumab, 9; nivolumab, 1) after progression on LMB-100 was 40%, and the median overall survival was 11.9 months. Of the seven evaluable patients, four had objective tumor responses, including one complete response and three partial responses, and the overall survival for these patients was 39.0+, 27.7, 32.6+, and 13.8 months. When stratified with regard to programmed death ligand 1 (PD-L1) expression, four of five patients with tumor PD-L1 expression had objective tumor response. Patients with positive tumor PD-L1 expression also had increased progression-free survival (11.3 versus 2.1 months, P = 0.0018) compared with those lacking PD-L1 expression. There was no statistically significant difference in overall survival (27.7 versus 6.8 months, P = 0.1). LMB-100 caused a systemic inflammatory response and recruitment of CD8+ T cells in patients' tumors. The enhanced antitumor effects with LMB-100 plus anti-PD-1 antibody were also observed in a human peripheral blood mononuclear cell-engrafted mesothelioma mouse model and a human mesothelin-expressing syngeneic lung adenocarcinoma mouse model. LMB-100 plus pembrolizumab is now being evaluated in a prospective clinical trial for patients with mesothelioma.

• Authors: Qun Jiang, Azam Ghafoor, Idrees Mian, Daniel Rathkey, Anish Thomas, Christine Alewine, Manjistha Sengupta, Mark A Ahlman, Jingli Zhang, Betsy Morrow, Seth M Steinberg, Ira Pastan, Raffit Hassan
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 550 (07 01 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 32611684 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• B7-H1 Antigen
• GPI-Linked Proteins
• Immunoconjugates
• Immunotoxins
• Msln protein, mouse
• LMB-100
• Mesothelin

Topics

• Animals
• B7-H1 Antigen
• CD8-Positive T-Lymphocytes
• GPI-Linked Proteins
• Humans
• Immunoconjugates
• Immunotoxins
• Leukocytes, Mononuclear
• Lung Neoplasms (drug therapy)
• Mesothelin
• Mesothelioma (drug therapy)
• Mice
• Prospective Studies