Enhanced Eradication of Lymphoma by Tumor-Specific Cytotoxic T-Cells Secreting an Engineered Tumor-Specific Immunotoxin

摘要

In this project, we postulate that tumor-specific T cells could be used to produce an immunotoxin (IT) targeting tumor cells only when these T cells are specifically activated by the tumor. We have engineered lentiviral vectors to modify tumor specific T cells with our immunotoxin. PEA based immunotoxins affect cell viability by ADP ribozilation of their elongation factor- 2. Indeed, we have also generated a producer cell line resistant to PEA in order to produce high titer of vector encoding the IT. We have first used cell lines to demonstrated that the IT could be produced, secreted, and that this secreted IT has a specific lethal activity toward CD22 target cells. We have then protected our T cells against the possible effects of endogenous IT and characterized several of their functions and phenotypes. Altogether, our data revealed that IT-producing tumor-specific T cells and IT-producing non specific T cells (OKT3-blast) efficiently produce IT and the IT secreted specifically kills CD22-tumor cells. Our data also showed that the IT released (by T cells) does not impair T cells original killing potential. Thus by allowing a double killing mechanism, our IT potentiates the eradication of CD22- tumors by T cells.