POLYNUCLEOTIDE IMMUNIZATION OF NONHUMAN-PRIMATES AGAINST CARCINOEMBRYONIC ANTIGEN

In preparation for a Phase I trial of DNA immunization against carcino embryonic antigen (CEA) in patients with colorectal carcinoma, we have produced a single plasmid DNA encoding CEA and hepatitis B surface an tigen (HBsAg) under transcriptional regulatory control of two separate cytomegalovirus promoters within separate eukaryotic expression casse ttes, designated pCEA/HBsAg, Hepatitis B surface antigen was included to provide an internal positive control for the efficacy of this immun ization strategy without regard to the issue of breaking tolerance to a self-antigen. In the present work, we sought to examine the immunoge nicity of this plasmid in a nonhuman primate model with close phylogen etic relationship to humans. Groups of pig-tailed macaques were immuni zed with pCEA/HBsAg by i.m. injection or particle bombardment of the s kin according to a dose and schedule thought to be optimal for the res pective technique of DNA immunization. Both administration techniques produced humoral and lymphoproliferative responses of comparable magni tude. However, delayed type hypersensitivity to CEA and CEA-specific i nterleukin-2 release were observed only in the i.m. group, suggesting a qualitative difference in the character of the immune response elici ted by the two techniques of DNA immunization, The antibody responses to CEA and HBsAg were surprisingly persistent in that all immunized an imals maintained moderate antibody titers against both antigens for mo re than 15 months after the last boost. No toxicity was observed durin g 2 years of follow-up, including no measurable levels of anti-DNA ant ibody. This antitumor immunization strategy is presently being examine d in patients with metastatic colorectal carcinoma using pCEA/HBsAg ad ministered by i.m. injection.