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

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.

• Authors: Ian M Zitron, Archana Thakur, Oxana Norkina, Geoffrey R Barger, Lawrence G Lum, Sandeep Mittal
• Journal: BMC cancer (BMC Cancer) Vol. 13 Pg. 83 (Feb 22 2013) ISSN: 1471-2407 [Electronic] England
• PMID: 23433400 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• CD3 Complex
• Cytokines

Topics

• Analysis of Variance
• Antibodies, Bispecific (immunology, therapeutic use)
• Brain Neoplasms (immunology, metabolism, therapy)
• CD3 Complex (immunology)
• Cell Lineage
• Cytokines (metabolism)
• Cytotoxicity Tests, Immunologic
• Glioblastoma (immunology, metabolism, therapy)
• Humans
• Immunotherapy (methods)
• Lymphocyte Activation
• T-Lymphocytes, Cytotoxic (immunology)