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Replication-deficient adenoviruses (rec-AdV) expressing different transgenes are widely employed vectors for gene therapy and vaccination. We examined here the generation of β-galactosidase (βgal)-specific CTL following administration of βgal-recombinant adenovirus (AdLacZ). Using MHC class I tetramers to track βgal-specific CTL in different organs, we found that a significant expansion of βgal-specific CTL could only be achieved in a very narrow dose range (2 × 108 – 2 × 109 pfu). Functional analysis revealed that adenovirus-induced βgal-specific CTL produced only very low amounts of effector cytokines and were unable to lyse βgal peptide-pulsed target cells. Injection of optimal doses of Ad-LacZ into transgenic mice which express βgal exclusively in non-lymphoid organs, led to physical deletion of βgal-specific CTL. Our results indicate first that CTL deletion in the course of adenoviral vaccination is preceded by their functional impairment and second, that the outcome of rec-AdV vaccination depends critically on the antigen load in peripheral tissues. The presented findings thus impinge on the rationale to use adenoviral vectors in clinical vaccination. from Association for Immunotherapy of Cancer: Cancer Immunotherapy – 2nd Annual Meeting Mainz, Germany, 6–7 May 2004

Rapid functional exhaustion and deletion of cytotoxic T lymphocytes following immunization with recombinant adenovirus