Phase I Immunotherapy Trial with Two Chimeric HER-2 B-Cell Peptide Vaccines Emulsified in Montanide ISA 720VG and Nor-MDP Adjuvant in Patients with Advanced Solid Tumors
Phase I Immunotherapy Trial with Two Chimeric HER-2 B-Cell Peptide Vaccines Emulsified in Montanide ISA 720VG and Nor-MDP Adjuvant in Patients with Advanced Solid Tumors
复制标题
DOI：
10.1158/1078-0432.ccr-18-3997
复制
发表时间：
2019-06-15
影响因子：
11.5
通讯作者：
Kaumaya, Pravin T. P.
中科院分区：
文献类型：
--
作者：
Bekaii-Saab, Tanios;Wesolowski, Robert;Kaumaya, Pravin T. P.
目的：这项首次人体I期研究（NCT 01417546）评估了两种肽b细胞表位疫苗组合的安全性、最佳免疫/生物剂量（OID/OBD）和免疫原性，这些疫苗被设计为代表曲妥珠单抗和帕妥珠单抗结合位点。尽管曲妥珠单抗和帕妥珠单抗已被批准用于临床，但患者经常对这些疗法产生耐药性。我们已经提出了一种新的免疫治疗模式，其重点是基于构象b细胞表位疫苗的体液反应。患者和方法：该疫苗由两种嵌合HER-2 b细胞肽疫苗组成，其中含有“混杂t细胞表位”。在Montanide ISA 720VG油包水载体中，用非muramyldipeptide佐剂乳化的疫苗构建物对患者进行免疫。符合条件的转移性和/或复发性实体瘤患者每3周接种3次。结果：49例既往化疗中位数为4线的患者接受了至少1次疫苗接种。28名患者完成了3种疫苗接种方案。6例患者在治疗后接受了1个月的强化治疗，1例患者接受了7个月的强化治疗。未观察到严重的不良反应或剂量限制性毒性。该疫苗耐受良好，剂量水平2为推荐的II期剂量。所有患者中最常见的相关毒性是注射部位反应（24%）。2例患者部分缓解，14例病情稳定，19例病情进展。结论：该疫苗是安全的，具有抗肿瘤活性，初步表明多肽疫苗可避免治疗耐药性，是单克隆抗体治疗的一个有希望的替代方案。
Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab-and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines.Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a "promiscuous T-cell epitope." Patients were immunized with the vaccine constructs emulsified with nor-muramyldipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks.Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease.Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.