Regulation of T-helper-1 versus T-helper-2 activity and enhancement of tumor immunity by combined DNA-based vaccination and nonviral cytokine gene transfer

Intramuscular (i.m.) injections of a plasmid encoding human carcinoembryoni c antigen (CEA) elicited both humoral and cellular immune responses in mice , but only partial inhibition of the growth of transplanted syngeneic CEA-p ositive P815 tumor cells (CEA/P815). Coinjection of the CEA vector with a v ector encoding either interferon-gamma (IFN gamma) or IL-12 promoted IgG2a isotype anti-CEA antibody production, anti-CEA/P815 CTL activity and greate r resistance to CEA/P815 tumor challenge. As well, CEA/P815-stimulated IFN gamma secretion in vitro was increased, but IL-4 diminished, consistent wit h a T-helper type 1 (Th1) response. in contrast, coinjection of the CEA vec tor with an IL-4 vector increased IgG1 production, but reduced CTL activity and resistance to tumor challenge. The latter treatment inhibited CEA/P815 -dependent IFN gamma production but enhanced IL-4 secretion, consistent wit h a Th type 2 (Th2) response. Antitumor immunity was enhanced when the CEA and IL-12 plasmids were coinjected at the same muscle site, but not at sepa rate sites despite increased serum IL-12 levels. Though the tumor cells exp ressed neomycin phosphotransferase, mice immunized with vectors encoding th at protein (without CEA) were not protected against tumor growth, and produ ced no CTLs except for low levels when coinjected with an IL-12 vector. Thu s, we show that immunity elicited by DNA vaccination against CEA can be bia sed to a protective type (high Th1 and CTL activity) or nonprotective type (high Th2 and low CTL activity) by im. coinjection of cytokine-expressing p lasmids. IL-12 appears to act locally, but not systemically, through an adj uvant effect.