Special Issue "Immunotoxins—A Special Issue Devoted to Combination Approaches for Cancer Treatment"

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (15 December 2017) | Viewed by 5735

Special Issue Editor

Dr. David J. Fitzgerald
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Guest Editor
Laboratory of Molecular Biology, CCR, NCI, NIH, HHS, 37 Convent Dr, Room 5124, Bethesda, MD, 20892, USA
Interests: antibodies; toxins; cancer therapeutics; cell biology; immunotoxins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antibody-toxin or ligand-toxin proteins (here generically called ‘immunotoxins’) have been used extensively to bind and kill cancer cells. In this regard, these cytotoxic chimeric proteins are targeted to particular surface proteins and thereby gain entry to the cell interior where they shut down the host cell protein synthetic machinery. In rare instances, this simple strategy has led to complete clinical remissions benefitting a small number of cancer patients. However, more often than not, the injection of an immunotoxin produces only a partial response indicating that additional agents are needed to enhance antitumor activity. To highlight one avenue of improvement, the next Special Issue on Immunotoxins will focus on combination therapies where the immunotoxin ‘platform’ is joined with other agents with the goal of achieving better outcomes. Combination treatments can be developed in tissue culture systems, immunological models, tumor models or as part of a clinical trial. With the advent of large drug libraries, immunotherapy, checkpoint inhibitors and vaccines, combination strategies can follow a number of highly interesting directions.

Guest Editor
Dr. David J. Fitzgerald

Manuscript Submission Information

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Keywords

  • toxin
  • immunotoxin
  • cancer
  • combination
  • checkpoint
  • vaccine
  • tumor
  • microenvironment
  • antidrug
  • antibodies
  • immunotherapy

Published Papers (2 papers)

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Research

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Article
Development of a Deimmunized Bispecific Immunotoxin dDT2219 against B-Cell Malignancies
Toxins 2018, 10(1), 32; https://doi.org/10.3390/toxins10010032 - 06 Jan 2018
Cited by 15 | Viewed by 2383
Abstract
Diphtheria toxin (DT) related targeted toxins are effective in cancer treatment, but efficacy diminishes in time because of their immunogenic potential and/or former vaccinations. In order to overcome this limitation for DT2219, a promising bispecific targeted toxin which targets CD19 and CD22, we [...] Read more.
Diphtheria toxin (DT) related targeted toxins are effective in cancer treatment, but efficacy diminishes in time because of their immunogenic potential and/or former vaccinations. In order to overcome this limitation for DT2219, a promising bispecific targeted toxin which targets CD19 and CD22, we deimmunized the DT moiety, and thereby developed an exciting improved drug (dDT2219) which still has the potential to sufficiently target B-cell malignancies but also limits clearance because of its reduced immunogenicity. The DT moiety was modified by inducing point mutations in prominent positions on the molecular surface. The new engineered dDT2219 was tested for activity, efficacy, and specificity using functional assays, proliferation assays, and flow cytometry. Furthermore, 12 samples of Chronic Lymphatic Leukemia (CLL) patients were used to assess binding. Immunogenicity was determined using a BALB/c mouse model. dDT2219 was efficient and specific against B-cell malignancies such as Bukitt-Lymphoma cell lines Daudi and Raji. dDT2219 showed specific binding on targets and on CLL samples. Intraperitoneal vaccination of immune competent mice showed that even after multiple administrations with increasing doses, induction of neutralizing antibodies was significantly lower in the dDT2219 treated animal group. The new dDT2219 combines potent anti-tumor cell activity with a reduced immunogenicity. With regard to the frequent development of neutralizing antibodies after multiple administrations with immunotoxins, dDT2219 shows promise to overcome this limitation and thus might maintain effectiveness even after multiple treatment cycles. Full article
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Review

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Review
Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins
Toxins 2018, 10(2), 82; https://doi.org/10.3390/toxins10020082 - 13 Feb 2018
Cited by 32 | Viewed by 3117
Abstract
Plant Ribosome-inactivating proteins (RIPs) including the type I RIP Saporin have been used for the construction of Immunotoxins (ITxs) obtained via chemical conjugation of the toxic domain to whole antibodies or by generating genetic fusions to antibody fragments/targeting domains able to direct the [...] Read more.
Plant Ribosome-inactivating proteins (RIPs) including the type I RIP Saporin have been used for the construction of Immunotoxins (ITxs) obtained via chemical conjugation of the toxic domain to whole antibodies or by generating genetic fusions to antibody fragments/targeting domains able to direct the chimeric toxin against a desired sub-population of cancer cells. The high enzymatic activity, stability and resistance to conjugation procedures and especially the possibility to express recombinant fusions in yeast, make Saporin a well-suited tool for anti-cancer therapy approaches. Previous clinical work on RIPs-based Immunotoxins (including Saporin) has shown that several critical issues must be taken into deeper consideration to fully exploit their therapeutic potential. This review focuses on possible combinatorial strategies (chemical and genetic) to augment Saporin-targeted toxin efficacy. Combinatorial approaches may facilitate RIP escape into the cytosolic compartment (where target ribosomes are), while genetic manipulations may minimize potential adverse effects such as vascular-leak syndrome or may identify T/B cell epitopes in order to decrease the immunogenicity following similar strategies as those used in the case of bacterial toxins such as Pseudomonas Exotoxin A or as for Type I RIP Bouganin. This review will further focus on strategies to improve recombinant production of Saporin-based chimeric toxins. Full article
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