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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2018.00553

A complement-independent mechanism for HUS induced by Pseudomonas immunotoxins

 Monika Bokori-Brown1*,  Jeremy Metz1,  Peter G. Petrov2,  Francis Mussai3, Carmela De Santo3, Neil J. Smart4, Sarah Saunders4, Bridget Knight4,  Ira Pastan5,  Richard W. Titball1 and C P. Winlove2
  • 1Biosciences, College of Life and Environmental Sciences, University of Exeter, United Kingdom
  • 2Departments of Physics and Astronomy, College of Engineering, Mathematics and Physical Sciences, University of Exeter, United Kingdom
  • 3Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
  • 4Royal Devon & Exeter NHS Foundation Trust, United Kingdom
  • 5Center for Cancer Research (NCI), United States

Acute Lymphoblastic Leukaemia (ALL) remains the most frequent cause of cancer-related mortality in children and novel therapies are needed for the treatment of relapsed/refractory childhood ALL. One approach is the targeting of ALL blasts with the Pseudomonas immunotoxin CAT-8015. Although CAT-8015 has potent anti-leukaemia activity, with a 32 % objective response rate in a phase 1 study of childhood ALL, haemolytic-uremic syndrome (HUS) and vascular leak syndrome (VLS), major dose-limiting toxicities, have limited the use of this therapeutic approach in children. Investigations into the pathogenesis of CAT-8015-induced HUS/VLS are hindered by the lack of an adequate model system that replicates clinical manifestations, but damage to vascular endothelial cells (ECs) and blood cells are believed to be major initiating factors in both syndromes. Since there is little evidence that murine models replicate human HUS/VLS, and CAT-8015-induced HUS/VLS predominantly affects children, we developed human models and used novel methodologies to investigate CAT-8015 interactions with red blood cells (RBCs) from paediatric ALL patients and ECs of excised human mesenteric arteries. We provide evidence that CAT-8015 directly interacts with RBCs, mediated by Pseudomonas toxin. We also show correlation between the electrical properties of the RBC membrane and RBC susceptibility to CAT-8015-induced lysis, which may have clinical implication. Finally, we provide evidence that CAT-8015 is directly cytototoxic to ECs of excised human mesenteric arteries. In conclusion, the human models we developed constitutes the first, and very important, step in understanding the origins of HUS/VLS in immunotoxin therapy and will allow further investigations of HUS/VLS pathogenesis.

Keywords: immunotoxin, Paediatric acute lymphoblastic leukaemia, red blood cell, HUS (hemolytic uremic syndrome), VLS, Moxetumomab pasudotox

Received: 16 Aug 2018; Accepted: 08 Nov 2018.

Edited by:

Rimas J. Orentas, Seattle Children's Research Institute, United States

Reviewed by:

Vernon L. Tesh, College of Medicine, Texas A&M University, United States
Robbie Majzner, School of Medicine, Stanford University, United States  

Copyright: © 2018 Bokori-Brown, Metz, Petrov, Mussai, De Santo, Smart, Saunders, Knight, Pastan, Titball and Winlove. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Monika Bokori-Brown, Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, EX4 4QD, England, United Kingdom, m.bokori-brown@exeter.ac.uk