Induction of cytotoxic T cells and their antitumor activity in mice transgenic for carcinoembryonic antigen

In order to develop immunotherapy strategies that are based on eliciting im mune responsiveness to the self-antigen, human carcinoembryonic antigen (CE A), we examined whether cytotoxic T lymphocyte (CTL) activity against CEA c ould be elicited in CEA-transgenic and nontransgenic mice. CEA-transgenic [ C57BL/6-TGN(CEAGe)18FJP] and nontransgenic mice were primed with CEA-transf ected syngeneic fibroblasts in combination with Corynebacterium parvum. Spl een cells from immunized mice were cultured with irradiated syngeneic MC-38 colon,carcinoma cells transfected with CEA (MC-38.CEA) as stimulators prio r to the measurement of CTL activity. Primed nontransgenic spleen cells sho wed augmented CTL activity against MC38.CEA cells as compared with control parental MC-38 cells, nontransfected or transfected with vector only. Moreo ver, primed CEA transgenic spleen cells showed augmented CTL activity again st MC-38.CEA cells that was similar to that observed in nontransgenic mice. All CTL clones derived from either transgenic or non-transgenic mice showe d cross-reactivity with MC-38 cells expressing the CEA-related antigen, non specific cross-reacting antigen, but not biliary glycoprotein. CEA-specific CTL clones were not identified. Adoptive transfer of cloned CTL resulted i n inhibition of MC38.CEA but not MC-38.BGP tumor growth. Tumor cures were e licited in mice treated with a combination of cloned CTL and cyclophosphami de. Histopathological examination of CEA-expressing colons from either immu nized mice or recipients of cloned CTL did not reveal any autoimmune reacti ons. These studies demonstrate that CTL recognizing cross-reactive class I epitopes on the CEA molecule can be induced in transgenic mice. The express ion of these epitopes on tumor cells creates effective targets for CTL in v ivo without inducing adverse reactions in CEA-expressing normal tissues. Si nce anti-CEA CTL have been generated in humans, CEA-transgenic mice may be a useful model to study vaccines that are based on CTL effector mechanisms.