Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors

Our plain-English summary of Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors, by B.L. Hagerty, G.J. Pegna, J. Xu, et al (Biomolecules, 2020).

The study

• Authors: B.L. Hagerty, G.J. Pegna, J. Xu, C.H. Tai, C. Alewine
• Journal: Biomolecules
• Published: 2020;10(7)
• Type of article: Review
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox's has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox's. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.

In plain English

This was a narrative review from the authors' laboratory describing mesothelin (MSLN)-targeted recombinant immunotoxins (iToxs) for solid tumours, covering pre-clinical work and published and ongoing clinical trials of the Pseudomonas exotoxin-based agents SS1P and LMB-100. The authors summarised that SS1P showed in vitro IC50 values of 0.08–3.9 ng/mL against tumour cells from patients with peritoneal mesothelioma. In a phase I bolus infusion trial a maximum tolerated dose of 45 mcg/kg was established when given every other day for three doses; minor tumour responses were seen, and 19 of 33 evaluable patients had stable disease. Neutralising anti-drug antibodies developed after cycle 1 in 75% of patients on short infusion and 88% on long infusion. Adding SS1P to pemetrexed and cisplatin gave partial responses in 12 of 20 (60%) evaluable mesothelioma patients. With pentostatin plus cyclophosphamide, only 2 of 10 patients developed antibodies after cycle 1. For LMB-100 the single-agent mesothelioma MTD was 140 mcg/kg. The authors concluded these agents show promise but that anti-drug antibodies and toxicity remain major obstacles.

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: narrative review of pre-clinical and clinical literature
• Who was studied: No new patients were studied; the review covered laboratory and animal studies and clinical trials of MSLN-targeted immunotoxins in patients with mesothelioma, pancreatic, ovarian, gastric and other MSLN-expressing solid tumours
• Exposure: Mesothelin-targeted recombinant immunotoxins carrying Pseudomonas exotoxin payloads (SS1P, LMB-100 and related constructs), alone or with chemotherapy or immune-modulating drugs
• Main results:
  • SS1P in vitro potency against patient-derived peritoneal mesothelioma cells
  • Phase I bolus SS1P monotherapy: MTD 45 mcg/kg every other day for three doses; minor tumour responses seen and stable disease in 19 of 33 evaluable patients
  • Neutralising anti-drug antibodies after one cycle of SS1P in the two phase I dosing schedules (short infusion 75%, long infusion 88%)
  • SS1P plus pemetrexed and cisplatin in unresectable mesothelioma: partial response in 12 of 20 evaluable patients, 3 with stable disease; 90% developed ADAs by cycle 2
  • SS1P after pentostatin plus cyclophosphamide lymphodepletion in pre-treated mesothelioma: 2 of 10 patients developed ADAs after cycle 1; near complete responses in three of eight patients receiving two or more cycles
  • Single-agent LMB-100 in mesothelioma: maximum tolerated dose 140 mcg/kg
  • LMB-100 plus nab-paclitaxel in advanced pancreatic cancer: CA 19-9 fall in 7 of 17 evaluable patients and one radiologic partial response; 62% reached therapeutic Cmax on cycle 2
  • Nine mesothelioma patients received pembrolizumab after LMB-100; four had durable responses (one complete, three partial)
  • Toxicity pattern reported: pleuritis was the dose-limiting toxicity of SS1P, capillary leak syndrome that of LMB-100
• The authors' conclusion: The authors concluded that MSLN-targeted immunotoxins have shown promise pre-clinically and clinically for mesothelioma and pancreatic cancer, but that substantial challenges remain and future work should address anti-drug antibody formation, capillary leak syndrome and combination strategies
• Limitations the authors state:
  • Results of two LMB-100 trials were not available at the time of the review
  • Serositis cannot be studied in current animal models because the binding domains do not recognise mouse mesothelin
  • The mechanism of capillary leak syndrome remains unknown
  • Drug delivery into patient tumours has not been measured and detection methods are insensitive
  • The authors describe the post-LMB-100 pembrolizumab responses as anecdotal

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Glycoprotein, Serosal Surface, Parenchyma, Mesothelioma, Adenocarcinoma, Clinical Trial.

Related studies

• Dual B- and T-cell de-immunization of recombinant immunotoxin targeting mesothelin with high cytotoxic activity — R. Mazor, M. Onda, et al. (2016)
• Anti-Mesothelin Recombinant Immunotoxin Therapy for Colorectal Cancer — A. Cerise, T.K. Bera, et al. (2019)
• Recombinant Immunotoxin with T-cell Epitope Mutations That Greatly Reduce Immunogenicity for Treatment of Mesothelin-Expressing Tumors — R. Mazor, J. Zhang, et al. (2015)
• Mesothelin-targeted agents in clinical trials and in preclinical development — R.J. Kelly, E. Sharon, et al. (2012)
• Immunogenicity of therapeutic recombinant immunotoxins — R. Mazor, M. Onda, et al. (2016)
• Anti-mesothelin immunotoxin induces mesothelioma eradication, anti-tumor immunity, and the development of tertiary lymphoid structures — W. Liu, C.H. Tai, et al. (2022)

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