ALVAC-p53(Sanofi Pasteur SA)

Overexpression of p53 occurs in more than 50% of colorectal cancers. Therefore, p53 represents an attractive target antigen for immunotherapy. We assessed the safety of a canarypox virus encoding the human wild-type p53 gene given intravenously to end-stage colorectal cancer patients in a three-step dose escalation study aimed at inducing p53 immune responses. Patients with metastatic disease of p53-overexpressing colorectal cancers were vaccinated three times at 3-week intervals, each time with 10(6.5) CCID(50) (CCID(50)=cell culture infectious dose 50%; group 1, n=5), 10(7.0) CCID(50) (group 2, n=5) or 10(7.5) CCID(50) (group 3, n=6). Vital signs and the occurrence of adverse events were monitored and blood was analyzed for biochemical and hematological parameters as well as signs of auto-immune safety. In all, 16 patients were enrolled and 15 patients completed three vaccinations. No anaphylactic reaction or unwanted auto-immune reactions were observed. A total of 16 serious adverse events (SAEs) occurred: 10 in group 1, three in group 2 and three in group 3. All SAEs were tumor-related complications. There was no difference in the frequency of adverse events between the three groups, except for fever. Fever was the only vaccination-related adverse event consistently observed and was most frequent and outspoken in the group 3 patients. The majority was a grade 1 or 2 fever (93%) and grade 3 fever (7%) was observed in three patients of group 3. Some patients showed humoral and cellular responses against p53, following vaccinations. After having completed his initial treatment cycle, one patient (group 2) received a second treatment cycle of three doses of 10(7.5) CCID(50) and subsequently showed stable disease. All other patients showed progressive disease. We conclude that ALVAC-p53 can be administered intravenously to colorectal cancer patients without serious toxicity or pathological autoimmunity and can induce immune responses against p53.

p53 is over-expressed in approximately 50% of human cancers, and transfer of cytotoxic T lymphocytes (CTL) against wild-type p53 protects mice against p53-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-over-expressing 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-immunity to a self-antigen, we felt it was necessary to first evaluate safety in rhesus macaques. We found that three intravenous administrations of vCP207 at proportional doses up to 10x those proposed for humans produced no abnormalities in hematologic or clinical chemistry parameters. Serologic markers of autoimmunity and inflammation were unaffected, despite the >95% amino acid identity between human and rhesus p53. Pathological examination of numerous tissues yielded findings comparable to those in animals given placebo. Some animals showed anti-p53 antibody responses following vaccination, indicating that tolerance could be broken to some extent. However, with the exception of one animal with a possible delayed type hypersensitivity reaction to p53 protein, we did not see evidence for a cell-mediated response. The safety profile in monkeys with ALVAC-p53 provides encouragement for using such live, modified vectors via the intravenous route for human immunotherapy.