Anti-Tumor Activity of Genetically Redirected T Cells Against Orthotopic Kidney Cancer in Mice

ABSTRACT

In order to test the effectiveness of adoptive immunotherapy against renal cell carcinoma (RCC) in a mouse model relevant to human disease, we first generated two murine renal cell carcinoma cell lines expressing the human tumor-associated antigen erbB2 by genetic modification of the Renca and SIRCC cell lines. When injected into the kidneys of mice, these cell lines rapidly formed a primary kidney tumor that metastasized to lung, liver and various peritoneal locations. Tumor-specific mouse T cells were generated by genetic modification of splenic T cells in vitro. The transgene encoded a chimeric receptor (T-body) specific for erbB2, in which a single-chain (scFv) anti-erbB2 antibody was linked to T cell activation and costimulatory domains (scFv-erbB2-CD28-zeta), to enable tumor recognition in a major histocompatibility complex-independent manner. Gene-modified T cells expressed the T-body on their surface, and could respond specifically against erbB2-expressing tumor cells as demonstrated by secretion of interferon-gamma. Adoptive transfer of T-body-expressing T cells could lead to inhibition of primary tumor and metastases. Systemic delivery of these gene-modified T cells led to complete eradication of disease in a proportion of mice, and this was associated with peri-vascular tissue inflammation composed of activated lymphoid cells, with macrophages and lesser numbers of eosinophils and neutrophils. This study demonstrated, for the first time, the efficacy of genetically redirected T cells against orthotopic renal cell carcinoma in mice.

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