Pilot study of a heptavalent vaccine-keyhole limpet hemocyanin conjugate plus QS21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer
Pilot study of a heptavalent vaccine-keyhole limpet hemocyanin conjugate plus QS21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer
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DOI：
10.1158/1078-0432.ccr-06-2949
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发表时间：
2007-07-15
影响因子：
11.5
通讯作者：
Livingston, Philip O.
中科院分区：
文献类型：
--
作者：
Sabbatini, Paul J.;Ragupathi, Govind;Livingston, Philip O.
目的：表征七价抗原-匙孔血蓝蛋白 (KLH) 加 QS21 疫苗构建体在第二次或多次完全临床缓解的上皮性卵巢癌、输卵管癌或腹膜癌患者中的安全性和免疫原性。 实验设计：该试点试验中的 11 名患者皮下注射了七价疫苗。含有 GM2 (10 μg)、Globo-H (10 μg)、LewisY (10 μg)、Tn(c) (3 μg)、STn(c) (3 μg)、TF(c) (3 μg) 和 Tn-MUC1 (3 μg)，分别与 KLH 缀合并与佐剂 QS21 (100 μg) 混合。在第 1、2、3、7 和 15 周进行疫苗接种。定期采集血液和尿液样本以监测安全性（全血细胞计数、综合检测、淀粉酶、促甲状腺激素和尿液分析）和抗体产生（ELISA、荧光激活细胞分选和补体依赖性细胞毒性）。结果：11 名患者纳入安全性分析； 11 名患者中有 9 名在第四次疫苗接种后仍继续研究至少 2 周，并被纳入免疫学分析（两名患者退出，疾病进展）。该疫苗耐受性良好。最常见的是自限性和轻度疲劳（两名患者最高为 2 级）、发烧、肌痛和局部注射部位反应。没有发现临床相关的血液学异常。没有发现自身免疫的临床或实验室证据。 ELISA 的血清学反应主要是针对每种抗原的 IgM，但 Tn-MUC1 除外，Tn-MUC1 会诱导 IgM 和 IgG 反应。免疫前抗体反应通常检测不到。免疫后，中位IgM滴度如下：Tn-MUC1，1：640（IgG 1：80）； TN，1：160； TF，1：640；环球-H，1:40；和 STn，1:80。仅看到一种针对 LewisY 的回应；两个人反对GM2。九名患者中有八名对至少三种抗原产生了反应。所有患者的抗体滴度在第 4 至第 8 周达到峰值。荧光激活细胞分选和补体依赖性细胞毒性分析显示，9 名患者中的 7 名针对 MCF7 细胞的反应性显着增加，所有患者中均出现一定程度的增加。 结论：这种七价 KLH 缀合物加上 QS21 疫苗可安全诱导针对 7 种抗原中的 5 种的抗体反应。有必要进行充分有力的疗效试验的调查。
Purpose: To characterize the safety and immunogenicity of a heptavalent antigen-keyhole limpet hemocyanin (KLH) plus QS21 vaccine construct in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in second or greater complete clinical remission.Experimental Design: Eleven patients in this pilot trial received a heptavalent vaccine s.c. containing GM2 (10 mu g), Globo-H (10 mu g), LewisY (10 mu g), Tn(c) (3 mu g), STn(c) (3 mu g), TF(c) (3 mu g), and Tn-MUC1 (3 mu g) individually conjugated to KLH and mixed with adjuvant QS21 (100 mu g). Vaccinations were administered at weeks 1, 2, 3, 7, and 15. Periodic blood and urine samples were obtained to monitor safety (complete blood count, comprehensive panel, amylase, thyroid-stimulating hormone, and urinalysis) and antibody production (ELISA, fluorescence-activated cell sorting, and complement-dependent cytotoxicity).Results: Eleven patients were included in the safety analysis; 9 of 11 patients remained on study for at least 2 weeks past fourth vaccination and were included in the immunologic analysis (two withdrew, disease progression). The vaccine was well tolerated. Self-limited and mild fatigue (maximum grade 2 in two patients), fever, myalgia, and localized injection site reactions were most frequent. No clinically relevant hematologic abnormalities were noted. No clinical or laboratory evidence of autoimmunity was seen. Serologic responses by ELISA were largely IgM against each antigen with the exception of Tn-MUC1 where both IgM and IgG responses were induced. Antibody responses were generally undetectable before immunization. After immunization, median IgM titers were as follows: Tn-MUC1,1:640 (IgG 1:80); Tn, 1:160; TF, 1:640; Globo-H, 1:40; and STn, 1:80. Only one response was seen against LewisY; two were against GM2. Eight of nine patients developed responses against at least three antigens. Antibody titers peaked at weeks 4 to 8 in all patients. Fluorescence-activated cell sorting and complement-dependent cytotoxicity analysis showed substantially increased reactivity against MCF7 cells in seven of nine patients, with some increase seen in all patients.Conclusions: This heptavalent-KLH conjugate plus QS21 vaccine safely induced antibody responses against five of seven antigens. Investigation in an adequately powered efficacy trial is warranted.