Characteristics of the specific humoral response in patients with advanced solid tumors after active immunotherapy with a VEGF vaccine, at different antigen doses and using two distinct adjuvants
Characteristics of the specific humoral response in patients with advanced solid tumors after active immunotherapy with a VEGF vaccine, at different antigen doses and using two distinct adjuvants
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不同抗原剂量和两种不同佐剂的 VEGF 疫苗主动免疫治疗后晚期实体瘤患者的特异性体液反应特征
作者：
J. Sánchez Ramírez;Yanelys Morera Díaz;Monica Bequet Romero;F. Hernández;Katty;Ana Victoria de la Torre Santos;Eduardo Rafael Santiesteban Álvarez;Yenima Martín Bauta;Cimara H. Bermúdez Badell;Josué de la Torre Pupo;J. Gavilondo;Marta Ayala Ávila
CIGB-247是一种含VSSP佐剂的VEGF疫苗，在晚期实体瘤患者（CENTAURO）的I期临床试验中进行了评估。用最大剂量的抗原接种显示出极好的安全性特征，表现出最高的免疫原性，并且是唯一显示血小板VEGF生物利用度降低的疫苗。然而，该抗原剂量水平在接种疫苗的患者中未达到完全血清转化率。这些临床结果使我们产生了一个问题，即在癌症患者中是否存在针对VEGF的未开发的免疫应答潜力的“储备”。为了解决这一问题，进行了CENTAURO-2临床试验，其中研究了抗原和VSSP剂量放大，并且还结合了磷酸铝作为佐剂的探索。进行这些改变的目的是增加针对VEGF的免疫应答。本研究报告了由CIGB-247从不同抗原剂量和佐剂的组合引起的体液应答的表征。对癌症患者进行了约1年的免疫学监测。用不同的CIGB-247制剂进行的疫苗接种表现出非常积极的安全性特征。癌症患者产生了对VEGF特异性的IgM、IgG或伊加抗体。诱导的多克隆抗体具有阻断VEGF及其受体VEGFR 1和VEGFR 2之间相互作用的能力。以800 μg抗原+200 μg VSSP免疫的患者检测到最高的体液应答。不按方案长期接种疫苗不会产生体液应答的负面变化。用人VEGF变体分子作为抗原与VSSP或磷酸铝组合的疫苗接种是免疫原性的。本研究的结果可能有助于在充分有效的功效试验中对这种疫苗疗法进行调查。试验注册号：RPCEC 00000155。古巴公共临床试验注册中心。注册日期：2013年6月6日。可从以下网址获得：http://registroclinico.sld.cu/
CIGB-247, a VSSP-adjuvanted VEGF-based vaccine, was evaluated in a phase I clinical trial in patients with advanced solid tumors (CENTAURO). Vaccination with the maximum dose of antigen showed an excellent safety profile, exhibited the highest immunogenicity and was the only one showing a reduction on platelet VEGF bioavailability. However, this antigen dose level did not achieve a complete seroconversion rate in vaccinated patients. These clinical results led us to the question whether a “reserve” of untapped immune response potential against VEGF could exist in cancer patients. To address this matter, CENTAURO-2 clinical trial was conducted where antigen and VSSP dose scale up were studied, and also incorporated the exploration of aluminum phosphate as adjuvant. These changes were made with the aim to increase immune response against VEGF. The present study reports the characterization of the humoral response elicited by CIGB-247 from the combining of different antigen doses and adjuvants. Cancer patients were immunologically monitored for approximately 1 year. Vaccination with different CIGB-247 formulations exhibited a very positive safety profile. Cancer patients developed IgM, IgG or IgA antibodies specific to VEGF. Elicited polyclonal antibodies had the ability to block the interaction between VEGF and its receptors, VEGFR1 and VEGFR2. The highest humoral response was detected in patients immunized with 800 μg of antigen + 200 μg of VSSP. Off-protocol long-term vaccination did not produce negative changes in humoral response. Vaccination with a human VEGF variant molecule as antigen in combination with VSSP or aluminum phosphate is immunogenic. The results of this study could contribute to the investigation of this vaccine therapy in an adequately powered efficacy trial. Trial registration number: RPCEC00000155. Cuban Public Clinical Trial Registry. Date of registration: June 06, 2013. Available from: http://registroclinico.sld.cu/.
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DOI：
10.1073/pnas.1416276112
发表时间：
2015-02-10
影响因子：
11.1
作者：
Seifert, Marc;Przekopowitz, Martina;Kueppers, Ralf
通讯作者：
Kueppers, Ralf
通过免疫球蛋白-A Fc 受体内化的卵清蛋白的呈现通过 Fc 受体伽马链信号传导得到增强。
影响因子：
20.3
作者：
Shen,L;vanEgmond,M;Siemasko,K;Gao,H;Wade,T;Lang,ML;Clark,M;vanDeWinkel,JG;Wade,WF
通讯作者：
Wade,WF
影响因子：
45.3
作者：
Kopetz, Scott;Hoff, Paulo M.;Heymach, John V.
通讯作者：
Heymach, John V.
影响因子：
45.3
作者：
Zhu, Andrew X.;Sahani, Dushyant V.;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
45.3
作者：
Willett, Christopher G.;Duda, Dan G.;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.