Successful elimination of large established tumors and avoidance of antigen-loss variants by aggressive adoptive T cell immunotherapy

Abstract

Utilization of ex vivo-expanded epitope-specific cytotoxic T lymphocytes has become a clinical standard in the adoptive immunotherapy of tumors. One of the obstacles faced by T cell-based immunotherapy is the development of tumor immune-escape variants. Using our previously reported CMS5 tumor/DUC18 CD8(+) TCR transgenic system, we sought to investigate whether large established tumors can be successfully eliminated before the development of escape variants. Using BALB/c mice that were s.c. transplanted with two tumors that had been growing for 8 days (double 8-day tumors), we assessed the in vivo anti-tumor activity of in vitro peptide-stimulated DUC18 T cells. A single infusion of activated DUC18 T cells showed a modest effect against the double 8-day tumors, whereas two and three administrations led to regression of both tumors within 10 days. However, in some mice, the tumors re-grew approximately 10 days after the regression. We found these tumors to be antigen-loss variants. These relapsed tumor cells progressively grew in DUC18 transgenic mice and did not express tERK-specific message. When four doses of activated DUC18 T cells were infused, the double 8-day tumors were successfully eliminated and the tumors did not grow out in any mice. Our results demonstrate that mono-specific CD8(+) T cells can effectively eliminate large established tumors before the development of antigen-loss variants when a high number of T cells is rapidly administered.