一项在晚期癌症患者中使用多靶向重组腺病毒 5（CEA/MUC1/Brachyury）免疫治疗疫苗方案的 I 期临床试验。
A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)-Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer.
机构信息
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
出版信息
Oncologist. 2020 Jun;25(6):479-e899. doi: 10.1634/theoncologist.2019-0608. Epub 2019 Oct 8.
LESSONS LEARNED
Concurrent ETBX-011, ETBX-051, and ETBX-061 can be safely administered to patients with advanced cancer. All patients developed CD4 and/or CD8 T-cell responses after vaccination to at least one tumor-associated antigen (TAA) encoded by the vaccine; 5/6 patients (83%) developed MUC1-specific T cells, 4/6 (67%) developed CEA-specific T cells, and 3/6 (50%) developed brachyury-specific T cells. The presence of adenovirus 5-neutralizing antibodies did not prevent the generation of TAA-specific T cells.
BACKGROUND
A novel adenovirus-based vaccine targeting three human tumor-associated antigens-CEA, MUC1, and brachyury-has demonstrated antitumor cytolytic T-cell responses in preclinical animal models of cancer.
METHODS
This open-label, phase I trial evaluated concurrent administration of three therapeutic vaccines (ETBX-011 = CEA, ETBX-061 = MUC1 and ETBX-051 = brachyury). All three vaccines used the same modified adenovirus 5 (Ad5) vector backbone and were administered at a single dose level (DL) of 5 × 10 viral particles (VP) per vector. The vaccine regimen consisting of all three vaccines was given every 3 weeks for three doses then every 8 weeks for up to 1 year. Clinical and immune responses were evaluated.
RESULTS
Ten patients enrolled on trial (DL1 = 6 with 4 in the DL1 expansion cohort). All treatment-related adverse events were temporary, self-limiting, grade 1/2 and included injection site reactions and flu-like symptoms. Antigen-specific T cells to MUC1, CEA, and/or brachyury were generated in all patients. There was no evidence of antigenic competition. The administration of the vaccine regimen produced stable disease as the best clinical response.
CONCLUSION
Concurrent ETBX-011, ETBX-051, and ETBX-061 can be safely administered to patients with advanced cancer. Further studies of the vaccine regimen in combination with other agents, including immune checkpoint blockade, are planned.
经验教训
同时给予 ETBX-011、ETBX-051 和 ETBX-061 可安全用于晚期癌症患者。所有患者在接种疫苗后均至少针对一种由疫苗编码的肿瘤相关抗原（TAA）产生 CD4 和/或 CD8 T 细胞应答；6 名患者中有 5 名（83%）产生了 MUC1 特异性 T 细胞，6 名患者中有 4 名（67%）产生了 CEA 特异性 T 细胞，6 名患者中有 3 名（50%）产生了 brachyury 特异性 T 细胞。腺病毒 5 中和抗体的存在并不妨碍 TAA 特异性 T 细胞的产生。
背景
一种新型腺病毒为基础的疫苗针对三种人类肿瘤相关抗原-CEA、MUC1 和 brachyury-已在癌症的临床前动物模型中证明具有抗肿瘤细胞溶解 T 细胞应答。
方法
本开放标签、I 期试验评估了三种治疗性疫苗（ETBX-011 = CEA、ETBX-061 = MUC1 和 ETBX-051 = brachyury）的同时给药。所有三种疫苗均使用相同的修饰腺病毒 5（Ad5）载体骨架，并以 5×10 病毒粒子（VP）/载体的单一剂量水平（DL）给予。由所有三种疫苗组成的疫苗方案每 3 周给予一剂，然后每 8 周给予一剂，最长达 1 年。评估临床和免疫应答。
结果
10 名患者入组试验（DL1 = 6 名，其中 4 名在 DL1 扩展队列中）。所有与治疗相关的不良事件均为暂时性、自限性 1/2 级，包括注射部位反应和流感样症状。所有患者均产生了针对 MUC1、CEA 和/或 brachyury 的抗原特异性 T 细胞。没有证据表明存在抗原竞争。疫苗方案的给予产生了稳定的疾病作为最佳临床反应。
结论
同时给予 ETBX-011、ETBX-051 和 ETBX-061 可安全用于晚期癌症患者。计划进一步研究该疫苗方案与其他药物的联合应用，包括免疫检查点阻断。
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