PROTECTIVE ANTITUMOR IMMUNITY INDUCED BY VACCINATION WITH RECOMBINANTADENOVIRUSES ENCODING MULTIPLE TUMOR-ASSOCIATED CYTOTOXIC T-LYMPHOCYTE EPITOPES IN A STRING-OF-BEADS FASHION

Vaccines harboring genes that encode functional oncoproteins are intri nsically hazardous, as their application may lead to introduction of t hese genes into normal cells and thereby to tumorigenesis. On the othe r hand, oncoproteins are especially attractive targets for immunothera py of cancer, as their expression is generally required for tumor grow th, making the arisal of tumor variants lacking these antigens unlikel y. Using murine tumor models, we investigated the efficacy of polyepit ope recombinant adenovirus (rAd) vaccines, which encode only the immun ogenic T cell epitopes derived from several oncogenes, for the inducti on of protective anti-tumor immunity. We chose to employ rAd, as these are safe vectors that do not induce the side effects associated with, for example, vaccinia virus vaccines. A single polyepitope rAd was sh own to give rise to presentation of both H-2 and human leukocyte antig en-restricted cytotoxic T lymphocyte (CTL) epitopes. Moreover, vaccina tion with a rAd encoding H-2-restricted CTL epitopes, derived from hum an adenovirus type 5 early region 1 and human papilloma virus type 16- induced tumors, elicited strong tumor-reactive CTL and protected the v accinated animals against an otherwise lethal challenge with either of these tumors. The protection induced was superior compared with that obtained by vaccination with irradiated tumor cells. Thus, vaccination with polyepitope rAd is a powerful approach for the induction of prot ective anti-tumor immunity that allows simultaneous immunization again st multiple tumor-associated T cell epitopes, restricted by various ma jor histocompatibility complex haplotypes.