Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients
Safety of intravenous administration of a canarypox virus encoding the human wild-type p53 gene in colorectal cancer patients
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DOI：
10.1038/sj.cgt.7700600
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发表时间：
2003-07-01
影响因子：
6.4
通讯作者：
van de Velde, CJH
中科院分区：
文献类型：
--
作者：
Menon, AG;Kuppen, PJK;van de Velde, CJH
超过50%的结直肠癌中存在p53的过度表达。因此，p53代表了用于免疫治疗的有吸引力的靶抗原。我们在一项旨在诱导p53免疫应答的三步剂量递增研究中，评估了编码人类野生型p53基因的金丝雀痘病毒静脉注射给终末期结直肠癌患者的安全性。p53过度表达结直肠癌转移性疾病患者以3周间隔接种3次，每次接种10（6.5）CCID 50（CCID 50 =细胞培养感染剂量50%;组1，n=5）、10（7.0）CCID 50（组2，n=5）或10（7.5）CCID 50（组3，n=6）。监测生命体征和不良事件的发生，并分析血液的生化和血液学参数以及自身免疫安全性体征。共有16名患者入组，15名患者完成了三次疫苗接种。未观察到过敏反应或不必要的自身免疫反应。共发生16起严重不良事件（SAE）：第1组10起，第2组3起，第3组3起。所有SAE均为肿瘤相关并发症。除发热外，三组之间不良事件的频率没有差异。发热是唯一持续观察到的疫苗接种相关不良事件，在第3组患者中最为常见和直言不讳。大多数为1级或2级发热（93%），在第3组的3例患者中观察到3级发热（7%）。一些患者在接种疫苗后表现出对p53的体液和细胞反应。在完成初始治疗周期后，1例患者（组2）接受了第二个治疗周期（3剂10（7.5）CCID 50），随后显示疾病稳定。所有其他患者均显示疾病进展。我们的结论是，ALVAC-p53可以静脉注射给大肠癌患者，没有严重的毒性或病理性自身免疫，并能诱导针对p53的免疫应答。
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) CCID50 (CCID50=cell culture infectious dose 50%; group 1, n=5), 10(7.0) CCID50 (group 2, n=5) or 10(7.5) CCID50 (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) CCID50 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.