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EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose

Immunotoxins as anti-cancer therapeutics have several potential advantages over conventional agents including a high specificity, extraordinary potency, and a lack of an identified mechanism for resistance. It has been clearly demonstrated that Pseudomonas-based immunotoxins have a direct cytotoxic effect. However, delayed and often dramatic antitumor responses seen in human studies with targeted toxins led us to hypothesize that immunologic responses may be a secondary mechanism that enhances the therapeutic efficacy of these novel drugs.

Experimental design

This hypothesis was tested in a murine system using an immunotoxin, MR1-1 [MR1-1(dsFv)-PE38KDEL], that targets a syngeneic murine homologue of the tumor-specific human epidermal growth factor mutation, EGFRvIII, expressed on a murine cell line.

Results

Intratumoral treatment with MR1-1 eliminated EGFRvIII-expressing tumors (P < 0.0001). The antitumor activity of MR1-1 was dependent on the expression of EGFRvIII on some, but not all tumors cells, and was significantly inhibited in the absence of CD4+ (P = 0.0193) and CD8+ (P = 0.0193) T cells. MR1-1 induced EGFRvIII-specific immunity (P < 0.0005) and produced long lasting immunity against tumors expressing EGFRvIII as well as EGFRvIII-negative tumors.

Conclusions

These data suggest that immunotoxins may not be strictly dependent on direct cytotoxicity for their efficacy, but may also be potent inducers of antitumor immunity active even against cells that do not express the targeted antigen.

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Abbreviations

EGFRvIII:

Epidermal growth factor receptor variant III

Anti-Tac(dsFv)-PE38:

Anti-CD25(dsFv)-PE38KDEL immunotoxin

MR1-1:

MR1-1(dsFv)-PE38KDEL immunotoxin

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Acknowledgments

The work was supported by the following grants: 1P50 CA108786-01 (D. D. Bigner/J. H. Sampson), 2P50-NS20023-21 (D. D. Bigner/J. H. Sampson), 1R01 CA097222 (J. H. Sampson), 1R01 CA097611 (J. H. Sampson), K23 RR16065 (J. H. Sampson) along with support from the ABC2 Foundation (D. D. Bigner/J. H. Sampson) and the Sidney Kimmel Foundation for Cancer Research (Sampson). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (I. H. Pastan). We acknowledge the technical assistance of Tracy Chewning and editorial assistance of Shenell Summers.

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Authors and Affiliations

  1. Department of Surgery (Neurosurgery), Duke University Medical Center, Box 3050, Durham, NC, 27710, USA

    Hidenobu Ochiai, Gary E. Archer, Duane A. Mitchell, Darell D. Bigner & John H. Sampson

  2. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27710, USA

    James E. Herndon II

  3. Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA

    Chien-Tsun Kuan, Darell D. Bigner & John H. Sampson

  4. Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Ira H. Pastan

Authors
  1. Hidenobu Ochiai
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  2. Gary E. Archer
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  3. James E. Herndon II
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  4. Chien-Tsun Kuan
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  5. Duane A. Mitchell
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  6. Darell D. Bigner
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  7. Ira H. Pastan
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  8. John H. Sampson
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Correspondence to John H. Sampson.

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Ochiai, H., Archer, G.E., Herndon, J.E. et al. EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells. Cancer Immunol Immunother 57, 115–121 (2008). https://doi.org/10.1007/s00262-007-0363-7

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  • DOI: https://doi.org/10.1007/s00262-007-0363-7

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