Abstract 4775: HER-2 is expressed by all ovarian cancer cells and invariably recognized by genetically engineered HER-2 specific T cells
Authors: Lanitis Evripidis , Czerniecki Brian J. , Carroll Richard G. , Sandaltzopoulos Raphael , Coukos George , Powell Daniel J. 
Published: February 2011

Background: HER-2/neu protein has been repetitively reported to be overexpressed in 20-30% of epithelial ovarian cancer and is associated with relapsing after chemotherapy and poor survival. Thus, HER-2 represents an attractive candidate antigen for immunotherapy of cancer patients. While HER-2 specific T cells can be induced by vaccination or generated de novo by genetic engineering, it remains uncertain to what extent T cell-based “HER-2 directed” immunotherapy can be utilized for the treatment of advanced ovarian cancer.

Objective: To investigate the role of HER-2 as the resolute tumor antigen for T cell based adoptive immunotherapy of ovarian cancer.

Methods: HER-2 expression was analysed by Real Time PCR, flow cytometry and western blot in a large number of both establish and short-term cultured cancer cell lines and tumor cells derived from malignant ascites and solid tumor harvested from ovarian cancer patients. T cells with specificity against HER-2 were generated by two different ways: either by stimulating CD8+ T cells enriched from PBMC with monocyte-derived mature DC from patients vaccinated against HER-2 peptides; or by genetic engineering of CD4+ and CD8+T lymphocytes to express HER-2 specific chimeric immune receptors (CIRs) capable of redirecting potent non-MHC-dependent cytotoxicity to tumor cells expressing HER-2. HER-2 specific T cells were tested for their capacity to recognize and kill HER-2 expressing tumors.

Results: HER-2 overexpression was observed in all (13/13) established ovarian cancer cell lines and all 7/7 (100 %) short-term cultured cell lines. Consistent with these results, all primary ascites (n=22) and solid tumor (n=12) derived tumor cells tested expressed detectable levels of cell surface HER-2. To validate the role of HER-2 as a strong T cell target, natural HER-2 peptide-specific T cells with high functional avidity and CIR redirected T cells were tested for tumor reactivity. Genetically redirected T cells recognized all tested ovarian cancer cell targets (n=16), and were superior to naturally occurring HER-2 specific T cells which were functionally restricted by MHC haplotype and impaired antigen processing by tumor cells.

Conclusions: HER-2 is expressed by all ovarian cancer cells and invariably recognized by genetically engineered HER-2 specific T cells suggesting that targeting HER-2 may be more efficacious in patients with ovarian carcinoma than previously suggested by reports of 20-30% overexpression of HER-2 in primary ovarian tumors. These findings provide the rationale for the development of HER-2 redirected T cell-based immunotherapeutic approaches for ovarian cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4775.