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Low Levels of Her2/neu Expressed by Ewing's Family Tumor Cell Lines Can Redirect Cytokine-Induced Killer Cells

Authors' Affiliations: ¹ Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; and Departments of ² Medicine, ³ Pathology, and ⁴ Pediatrics, Stanford University, Stanford, California

Requests for reprints: Michael R. Verneris, Pediatric Blood and Marrow Transplantation, University of Minnesota, Room 660, Cancer Center Research Building, 425 East River Road, Minneapolis, MN 55455. Phone: 612-626-2408; E-mail: Verneris{at}UMN.edu.

Purpose: To identify novel treatments for pediatric solid tumors and/or for malignancies with low-level Her2/neu expression.

Experimental Design: Using fluorescence-activated cell sorting and immunohistochemistry, Her2/neu expression was determined on cell lines derived vfrom Ewing's family tumors (EFT) and neuroblastoma. Sensitivity to trastuzumab treatment was investigated using an in vitro proliferation assay. Cytotoxicity against EFT cell lines was done with either freshly isolated or ex vivo activated and expanded T cells (cytokine-induced killer cells, CIK cells), with or without addition of a CD3xHer2/neu bispecific antibody. The effects of either trastuzumab, CIK cells alone, or CD3xHer2/neu bispecific antibody redirected CIK cells was determined using a SCID/hu model of EFTs and serial, noninvasive bioluminescent imaging.

Results: EFT cell lines express 5- to 10-fold lower levels of her2/neu than either breast (BT-474) or ovarian (SK-OV-3) cell lines. Treatment of EFT cell lines with trastuzumab did not induce growth inhibition either in vitro or in vivo. In contrast, Her2/neu could be used to redirect CIK cell to mediate cytotoxicity against EFTs both in vitro and in vivo (using two different treatment schemas).

Conclusions: CD3xHer2/neu bispecific antibody and CIK cells may be a suitable approach to treat malignancies with low-level Her2/neu expression not responsive to trastuzumab.

Key Words: Ewing's sarcoma • immunotherapy • bispecific antibody • T cells • bioluminescent imaging

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