Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients

Abstract

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 endstage 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 ¼ cell culture infectious dose 50%; group 1, n ¼ 5), 10 7.0 CCID 50 (group 2, n ¼ 5) or 10 7.5 CCID 50 (group 3, n ¼ 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.

Induction of p53-Specific Immunity by a p53 Synthetic Long Peptide Vaccine in Patients Treated for Metastatic Colorectal Cancer

“…Primary endpoint of this study was safety and immunogenicity; secondary endpoint was tumor reactivity. Based on our previous clinical study, in which 2 of 5 patients injected with canary poxvirus with human wildtype p53 mounted a T-cell response (28,29), and based on our animal studies, in which the p53-SLP vaccine was able to induce immunity in all mice (13), as well as on the high number of cancer patients responding in our HPV16-SLP studies (38,39), it was expected that sufficient subjects in a group of 10 patients will show a p53-specific immune response to report on safety and immunogenicity. Eligibility required the following criteria: (a) performance status of WHO 0 to 1; (b) pretreatment laboratory findings of leukocytes >3 Â 10 9 /L, lymphocytes >1 Â 10 9 /L, platelets >100 Â 10 9 /L, hematocrit >30%, and hemoglobin >6 mmol/L; (c) no radiotherapy, chemotherapy, or other potentially immunosuppressive therapy administered within 4 weeks before the vaccination; (d) no history of autoimmune disease or systemic disease, which might affect immunocompetence; (e) no other malignancies (previous or current), except adequately treated basal or squamous cell carcinoma of the skin; (f) HIV and hepatitis B seronegative; and (g) a life expectancy of >6 months.…”

“…Several different antigen delivery systems have been tested to immunize patients against p53. In previous studies, an adenoviral vector encoding wild-type p53 (27), a recombinant canary poxvirus encoding wild-type p53 (28,29), or an adenoviral vector encoding wild-type p53-transfected dendritic cells (30) was used. These modalities were safe and capable of stimulating p53-specific T-cell responses in some of the vaccinated patients.…”

Synergistic anticancer effect of rAd/P53 combined with 5-fluorouracil or iodized oil in the early therapeutic response of human colon cancer in vivo

“…In experimental and phase I/II adenoviral p53 therapies for chemoradiation, resistance to advanced esophageal squamous cell carcinoma was observed (Shimada et al, 2006). Furthermore, treatment for colorectal carcinoma (Menon et al, 2003) and hepatocellular carcinoma (Guan et al, 2005(Guan et al, , 2007 showed that rAd/p53 increases the anticancer effects of chemotherapeutic agents. However, various questions need to be answered regarding Ad/ p53, such as whether the therapeutic effect of exogenous wt-p53 is inferior to that of exogenous wt-p53 gene combined with chemotherapy, and whether chemotherapeutic agents affect the activity of exogenous wt-p53 and how.…”

Immunologic aspect of ovarian cancer and p53 as tumor antigen

“…This strong anti adenoviral specific response may limit a p53 specific response. Based on the results in the mouse system[91,92,135] and rhesus macaques [136], a phase I/II clinical study involving vaccination of end-stage colorectal cancer patients with a recombinant canarypox virus (ALVAC) encoding wild type p53 was performed[137]. Patients were immunized intravenously with an increasing dosage of ALVAC-p53.…”