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Open Access Research article

Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

Ian M Zitron1, Archana Thakur2, Oxana Norkina2, Geoffrey R Barger3, Lawrence G Lum245 and Sandeep Mittal1*

Author Affiliations

1 Department of Neurosurgery, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA

2 Department of Oncology, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA

3 Department of Neurology, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA

4 Department of Medicine, Wayne State University, and Karmanos Cancer Institute, Detroit, MI, USA

5 Department of Immunology and Microbiology, Wayne State University, and Karmanos Cancer Institute, Detroit, MI, USA

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BMC Cancer 2013, 13:83  doi:10.1186/1471-2407-13-83

Published: 22 February 2013

Abstract

Background

Since most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2.

Methods

ATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3×anti-HER2/neu (HER2Bi) and/or anti-CD3×anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines.

Results

EGFRBi-armed ATC killed up to 85% of U87, U118, and U251 targets at effector:target ratios (E:T) ranging from 1:1 to 25:1. Engagement of tumor by EGFRBi-armed ATC induced Th1 and Th2 cytokine secretion by armed ATC. HER2Bi-armed ATC exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative U87 cells. HER2Bi- or EGFRBi-armed ATC exhibited 50—80% cytotoxicity against four primary glioblastoma lines as well as a temozolomide (TMZ)-resistant variant of U251. Both CD133– and CD133+ subpopulations were killed by armed ATC. Targeting both HER2Bi and EGFRBi simultaneously showed enhanced efficacy than arming with a single BiAb. Armed ATC maintained effectiveness after irradiation and in the presence of TMZ at a therapeutic concentration and were capable of killing multiple targets.

Conclusion

High-grade gliomas are suitable for specific targeting by armed ATC. These data, together with additional animal studies, may provide the preclinical support for the use of armed ATC as a valuable addition to current treatment regimens.

Keywords:
High-grade glioma; Adjuvant therapy; Immunotherapy; Activated T cells; Bispecific antibodies