Anti-Mesothelin Recombinant Immunotoxin Therapy for Colorectal Cancer

Our plain-English summary of Anti-Mesothelin Recombinant Immunotoxin Therapy for Colorectal Cancer, by A. Cerise, T.K. Bera, X. Liu, et al (Clinical Colorectal Cancer, 2019).

The study

• Authors: A. Cerise, T.K. Bera, X. Liu, J. Wei, I. Pastan
• Journal: Clinical Colorectal Cancer
• Published: 2019;18(3):192-199.e1
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Mesothelin (MSLN) is a cell surface glycoprotein expressed at a high level on many malignancies, including pancreatic adenocarcinoma, serous ovarian cancer, and epithelioid mesothelioma. MSLN-targeted recombinant immunotoxins (RITs) consist of an anti-MSLN Fv fused to the catalytic domain of Pseudomonas exotoxin A. Recent data has also shown that MSLN is expressed at clinically relevant levels on the surface of colorectal cancer (CRC). In this study, CRC cell lines were tested for MSLN expression and susceptibility to MSLN-targeted RITs.

Materials And Methods: CRC cell lines were tested for membranous MSLN expression via flow cytometry. Cell lines expressing MSLN were tested by WST-8 cell viability assay for sensitivity to various RITs and chemotherapeutic agents. CRC cell line SW-48 was tested in a mouse model for response to RIT as a single agent or in combination with actinomycin D and oxaliplatin.

Results: CRC cell lines were susceptible to anti-MSLN RITs at half maximal inhibitory concentration levels comparable with those previously described in pancreatic cancer cell lines. In a nude mouse model, MSLN-targeted RIT treatment of SW48 CRC tumors resulted in a significant decrease in tumor volume. Although combination therapy with standard of care chemotherapeutic oxaliplatin did not improve tumor regressions, combination therapy with actinomycin D resulted in > 90% tumor volume reduction with 50% complete regressions.

Conclusions: These data support the development of anti-MSLN RITs as well as other MSLN-targeted therapies for CRC.

Published by Elsevier Inc.

In plain English

This laboratory and mouse study tested whether drugs aimed at mesothelin, a protein on some cancer cells, could kill colorectal cancer cells. It did not study asbestos exposure or people with mesothelioma, which is mentioned only as background. The authors found mesothelin on the surface of two colorectal cancer cell lines, HTB39 and SW48. Three anti-mesothelin immunotoxins (LMB-12, LMB-100 and LMB-164), which join an antibody fragment to a bacterial toxin, killed both cell lines in culture. SW48 cells responded at doses similar to a pancreatic cancer cell line, KLM-1, and HTB39 cells were somewhat less sensitive. In female nude mice carrying SW48 tumors, LMB-100 or LMB-164 shrank tumors by 50% by Day 12. Adding actinomycin D to LMB-100 gave a 95% reduction in average tumor volume by Day 19, compared with 40% for LMB-100 alone. It also produced complete regressions in 13 of 22 mice. Adding oxaliplatin did not improve tumor shrinkage over LMB-100 alone, though the authors noted a slight growth delay with the combination. The authors concluded that this therapy has a previously overlooked role in colorectal cancer.

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 cell-culture experiments and mouse xenograft (animal) experiments
• Who was studied: Colorectal cancer cell lines HTB39 and SW48, compared with the KLM-1 pancreatic adenocarcinoma cell line. Female athymic nude mice aged 6 to 8 weeks carrying SW48 tumors, in groups of 8 or 22 animals according to the figure legends.
• Exposure: Anti-mesothelin recombinant immunotoxins LMB-12, LMB-100 and LMB-164, given alone or with actinomycin D (0.3 mg/kg) or oxaliplatin (4.2 mg/kg). In mice, LMB-100 was given at 2.5 mg/kg and LMB-164 at 0.3 mg/kg. LMB-11, which targets CD22, served as a negative control.
• Main results:
  • In SW48 cells, the half maximal inhibitory concentration (IC50) was 0.37 ng/mL for LMB-12, 0.78 ng/mL for LMB-100 and 0.55 ng/mL for LMB-164.
  • HTB39 cells were less sensitive than SW48 cells: the IC50 was 2.7 ng/mL for LMB-12 and LMB-100, and 5.7 ng/mL for LMB-164.
  • Immunotoxin sensitivity did not differ significantly between SW48 colorectal cells and KLM-1 pancreatic cells.
  • In mice, all tumors treated with LMB-100 or LMB-164 had regressed by 50% on Day 12. Vehicle-treated tumors grew exponentially over the same period.
  • Treated tumors took 13 days longer than vehicle-treated tumors to reach 300 mm3.
  • LMB-100 plus actinomycin D reduced average tumor volume by 95% by Day 19, compared with a 40% reduction for LMB-100 alone. Actinomycin D alone delayed growth, but the tumors did not regress.
  • The actinomycin D combination produced complete regressions in 13 of 22 treated mice.
  • Mice treated with LMB-100 plus actinomycin D had no significant weight loss. Actinomycin D alone caused some weight loss after the second dose.
  • In mice, tumor volume did not differ between LMB-100 alone and LMB-100 plus oxaliplatin. Neither treatment group had any complete regressions.
  • The authors noted that the oxaliplatin combination gave no added benefit apart from a slight growth delay.
  • Tumors in both the LMB-100 group and the LMB-100 plus oxaliplatin group reached 300 mm3 at 30 days. Vehicle-treated tumors reached that size at 6 days and oxaliplatin-only tumors at 8 days.
• The authors' conclusion: The authors concluded that mesothelin-targeted immunotoxin therapy has a previously overlooked role in colorectal cancer. They added that, combined with actinomycin D, it can produce significant tumor regression, including complete and durable regression.
• Limitations the authors state:
  • The colorectal tumors responded less well than KLM-1 pancreatic tumors had in an earlier study. The authors stated that the reason is unclear.
  • The authors suggested that oxaliplatin may have added no benefit because high enough levels could not be reached in the mice before toxicity occurred.
  • The authors stated that a large-scale study of the clinical and mutational implications of mesothelin expression in colorectal cancer still needs to be done.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Colorectal Cancer, Glycoprotein, Adenocarcinoma, Ovarian Cancer, Epithelioid, Mesothelioma.

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• An antimesothelin-monomethyl auristatin e conjugate with potent antitumor activity in ovarian, pancreatic, and mesothelioma models — S.J. Scales, N. Gupta, et al. (2014)
• Mesothelin-targeted agents in clinical trials and in preclinical development — R.J. Kelly, E. Sharon, et al. (2012)
• Mesothelin as a target for cervical cancer therapy — K. Jöhrens, L. Lazzerini, et al. (2019)
• Constitutive expression and anticancer potency of a novel immunotoxin onconase-DV3 — M. Sun, H. Tang, et al. (2016)

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