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Cancer Immunology, Immunotherapy

, Volume 57, Issue 1, pp 115–121 | Cite as

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

  • Hidenobu Ochiai
  • Gary E. Archer
  • James E. HerndonII
  • Chien-Tsun Kuan
  • Duane A. Mitchell
  • Darell D. Bigner
  • Ira H. Pastan
  • John H. SampsonEmail author
Original Article

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 (< 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+ (= 0.0193) and CD8+ (= 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.

Keywords

Astrocytoma Epidermal growth factor receptor Immunotherapy Immunotoxins T lymphocytes 

Abbreviations

EGFRvIII

Epidermal growth factor receptor variant III

Anti-Tac(dsFv)-PE38

Anti-CD25(dsFv)-PE38KDEL immunotoxin

MR1-1

MR1-1(dsFv)-PE38KDEL immunotoxin

Notes

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Hidenobu Ochiai
    • 1
  • Gary E. Archer
    • 1
  • James E. HerndonII
    • 2
  • Chien-Tsun Kuan
    • 3
  • Duane A. Mitchell
    • 1
  • Darell D. Bigner
    • 1
    • 3
  • Ira H. Pastan
    • 4
  • John H. Sampson
    • 1
    • 3
    Email author
  1. 1.Department of Surgery (Neurosurgery)Duke University Medical CenterDurhamUSA
  2. 2.Department of Biostatistics and BioinformaticsDuke University Medical CenterDurhamUSA
  3. 3.Department of PathologyDuke University Medical CenterDurhamUSA
  4. 4.Laboratory of Molecular BiologyNational Cancer Institute, NIHBethesdaUSA

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