Safety and immunogenicity of ALVAC wild-type human p53 (vCP207) by the intravenous route in rhesus macaques

p53 is over-expressed in similar to 50% of human cancers, and transfer of c ytutoxic T lymphocytes (CTL) against wild-type p53 protects mice against p5 3-over-expressing tumors, suggesting that p53 might be an attractive target for immunotherapy. Immunization of mice with a recombinant canarypox virus , ALVAC, expressing human wild-type p53 (vCP207) prevented growth of p53-ov er-exprssing tumors. Since intravenous administration induced better immune responses in mice than other routes, we have proposed to use this route in cancer patients. However, because this vector has never been administered intravenously to humans, and because of the possibility of inducing auto-im munity to a self-antigen, we felt it was necessary to first evaluate safety in rhesus macaques. We found that three intravenous administrations of vCP 207 at proportional doses up to 10 x those proposed for humans produced no abnormalities in hematologic or clinical chemistry parameters. Serologic ma rkers of autoimmunity and inflammation were unaffected, despite the > 95% a mino acid identity between human and rhesus p53. Pathological examination o f numerous tissues yielded findings comparable to those in animals given pl acebo. Some animals showed anti-p53 antibody responses following vaccinatio n, indicating that tolerance could be broken to some efficient. However, wi th the exception of one animal with a possible delayed type hypersensitivit y reaction to p53 protein, we did not see evidence for a cell-mediated resp onse. The safety profile in monkeys with ALVAC-p53 provides encouragement f or using such live, modified vectors via the intravenous route for human im munotherapy. (C) 2001 Elsevier Science Ltd. All rights reserved.