Immunogenicity of therapeutic recombinant immunotoxins

Our plain-English summary of Immunogenicity of therapeutic recombinant immunotoxins, by R. Mazor, M. Onda, I. Pastan (Immunological Reviews, 2016).

The study

• Authors: R. Mazor, M. Onda, I. Pastan
• Journal: Immunological Reviews
• Published: 2016;270(1):152-64
• Type of article: Review
• Cited by: 92 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Recombinant immunotoxins (RITs) are chimeric proteins designed to treat cancer. They are made up of an Fv or Fab that targets an antigen on a cancer cell fused to a 38-kDa portion of Pseudomonas exotoxin A (PE38). Because PE38 is a bacterial protein, it is highly immunogenic in patients with solid tumors that have normal immune systems, but much less immunogenic in patients with hematologic malignancies where the immune system is suppressed. RITs have shown efficacy in refractory hairy cell leukemia and in some children with acute lymphoblastic leukemia, but have been much less effective in solid tumors, because neutralizing antibodies develop and prevent additional treatment cycles. In this paper we will (i) review data from clinical trials describing the immunogenicity of PE38 in different patient populations; (ii) review results from clinical trials using different immunosuppressive drugs; and (iii) describe our efforts to make new less-immunogenic RITs by identifying and removing T- and B-cell epitopes to hide the RIT from the immune system.

Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

In plain English

This article was a review by National Cancer Institute researchers of immune reactions to recombinant immunotoxins, experimental cancer drugs that join an antibody fragment to part of a Pseudomonas bacterial toxin. It did not study asbestos exposure. The authors reviewed earlier clinical trials and laboratory studies, many from their own laboratory. The drug LMB-2 led to antibodies after the first cycle in 92% of melanoma patients but 17% of leukemia patients. In a reviewed trial of the mesothelin-targeting drug SS1P in pleural mesothelioma, 19/21 patients had neutralizing antibodies after the first cycle. Among 10 patients with refractory mesothelioma given SS1P with pentostatin and cyclophosphamide, 2/10 had antibodies after the first cycle and 6/10 after the second. One never made them and had 74% tumor shrinkage lasting more than 15 months. A modified drug, LMB-T20, showed an 81% decrease in immunogenicity compared with SS1P in T-cell laboratory tests. The authors stated they believe their new immunotoxins will be effective in cancer treatment, while noting that immunogenicity is not completely resolved.

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 clinical trials and laboratory studies (many from the authors' own laboratory) on the immunogenicity of Pseudomonas exotoxin-based recombinant immunotoxins
• Who was studied: Patients in previously published clinical trials with hematologic malignancies (e.g., hairy cell leukemia, acute lymphoblastic leukemia) and solid tumors (including pleural mesothelioma, melanoma, ovarian and other cancers). The review also covered laboratory studies in mice and in blood cells (PBMCs) from 50 naive donors.
• Exposure: Treatment with recombinant immunotoxins: an antibody fragment fused to a 38-kDa portion of Pseudomonas exotoxin A (PE38), alone or with immunosuppressive drugs. No asbestos exposure was studied.
• Main results:
  • LMB-2: 92% of melanoma patients made antibodies after the first treatment cycle, compared with 17% of immune-suppressed leukemia patients
  • SS1P in a reviewed pleural mesothelioma trial: 19/21 patients developed antibodies after cycle 1 and 21/21 overall (neutralization assay)
  • SS1P combined with pentostatin and cyclophosphamide in 10 refractory mesothelioma patients: 2/10 developed neutralizing antibodies after the first cycle and 6/10 after the second
  • In that combination trial, one patient never developed neutralizing antibodies over six cycles and had 74% tumor shrinkage maintained for more than 15 months
  • Moxetumomab pasudotox in hairy cell leukemia: 1/28 patients developed neutralizing antibodies after the first cycle and 10/28 during the entire trial
  • Across hundreds of patients treated with PE38-based immunotoxins, a single anaphylactic reaction was reported
  • The modified immunotoxin LMB-T20 had an 81% decrease in immunogenicity compared with SS1P, as assessed by T-cell activation analysis
• The authors' conclusion: The authors stated that they believe their new immunotoxins with B- or T-cell epitopes removed will be effective in cancer treatment.
• Limitations the authors state:
  • The deimmunized immunotoxins are a compromise between lower immunogenicity and drug potency, so immunogenicity is not completely resolved
  • B-cell epitope findings in mice may not apply to humans because mouse and human immune systems differ
  • Computer predictions of T-cell epitopes did not accurately match experimental results

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial.

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