多靶点重组 Ad5 PSA/MUC-1/ brachyury 基免疫治疗疫苗在转移性去势抵抗性前列腺癌（mCRPC）患者中的 I 期研究。
Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC).
机构信息
Genitourinary Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
Genitourinary Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
出版信息
J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2021-002374.
BACKGROUND
Antitumor vaccines targeting tumor-associated antigens (TAAs) can generate antitumor immune response. A novel vaccine platform using adenovirus 5 (Ad5) vectors [E1-, E2b-] targeting three TAAs-prostate-specific antigen (PSA), brachyury, and MUC-1-has been developed. Both brachyury and the C-terminus of MUC-1 are overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and have been shown to play an important role in resistance to chemotherapy, epithelial-mesenchymal transition, and metastasis. The transgenes for PSA, brachyury, and MUC-1 all contain epitope modifications for the expression of CD8+ T-cell enhancer agonist epitopes. We report here the first-in-human trial of this vaccine platform.
METHODS
Patients with mCRPC were given concurrently three vaccines targeting PSA, brachyury, and MUC-1 at 5×10 viral particles (VP) each, subcutaneously every 3 weeks for a maximum of three doses (dose de-escalation cohort), followed by a booster vaccine every 8 weeks for 1 year (dose-expansion cohort only). The primary objective was to determine the safety and the recommended phase II dose. Immune assays and clinical responses were evaluated.
RESULTS
Eighteen patients with mCRPC were enrolled between July 2018 and September 2019 and received at least one vaccination. Median PSA was 25.58 ng/mL (range, 0.65-1006 ng/mL). The vaccine was tolerable and safe, and no grade >3 treatment-related adverse events or dose-limiting toxicities (DLTs) were observed. One patient had a partial response, while five patients had confirmed PSA decline and five had stable disease for >6 months. Median progression-free survival was 22 weeks (95% CI: 19.1 to 34). Seventeen (100%) of 17 patients mounted T-cell responses to at least one TAA, whereras 8 (47%) of 17 patients mounted immune responses to all three TAAs. Multifunctional T-cell responses to PSA, MUC-1, and brachyury were also detected after vaccination in the majority of the patients.
CONCLUSIONS
Ad5 PSA/MUC-1/brachyury vaccine is well tolerated. The primary end points were met and there were no DLTs. The recommended phase II dose is 5×10 VP. The vaccine demonstrated clinical activity, including one partial response and confirmed PSA responses in five patients. Three patients with prolonged PSA responses received palliative radiation therapy. Further research is needed to evaluate the clinical benefit and immunogenicity of this vaccine in combination with other immuno-oncology agents and/or palliative radiation therapy.
TRIAL REGISTRATION NUMBER
NCT03481816.
背景
针对肿瘤相关抗原（TAA）的抗肿瘤疫苗可以产生抗肿瘤免疫反应。一种新型的腺病毒 5（Ad5）载体[E1-，E2b-]疫苗平台，针对三个 TAA-前列腺特异性抗原（PSA）、Brachyury 和 MUC-1-已被开发出来。Brachyury 和 MUC-1 的 C 端在转移性去势抵抗性前列腺癌（mCRPC）中过度表达，并且已被证明在化疗耐药、上皮-间充质转化和转移中发挥重要作用。PSA、Brachyury 和 MUC-1 的转基因均包含 CD8+T 细胞增强激动表位的表达修饰。我们在此报告该疫苗平台的首次人体试验。
方法
18 例 mCRPC 患者接受三种针对 PSA、Brachyury 和 MUC-1 的疫苗，每个疫苗剂量为 5×10 病毒颗粒（VP），皮下注射，每 3 周一次，最多 3 剂（剂量递减队列），然后每 8 周进行一次加强疫苗接种，持续 1 年（仅剂量扩展队列）。主要目的是确定安全性和推荐的 II 期剂量。评估免疫测定和临床反应。
结果
2018 年 7 月至 2019 年 9 月，共招募了 18 例 mCRPC 患者，他们至少接受了一次接种。中位 PSA 为 25.58ng/ml（范围：0.65-1006ng/ml）。疫苗耐受且安全，未观察到 3 级及以上与治疗相关的不良事件或剂量限制性毒性（DLT）。1 例患者有部分缓解，5 例患者有确认的 PSA 下降，5 例患者有超过 6 个月的稳定疾病。中位无进展生存期为 22 周（95%CI：19.1-34）。17 例（100%）患者对至少一种 TAA 产生了 T 细胞反应，而 17 例患者中有 8 例（47%）对所有三种 TAA 产生了免疫反应。接种疫苗后，大多数患者也检测到 PSA、MUC-1 和 Brachyury 的多功能 T 细胞反应。
结论
Ad5 PSA/MUC-1/Brachyury 疫苗具有良好的耐受性。主要终点达到，无 DLT。推荐的 II 期剂量为 5×10 VP。该疫苗显示出临床疗效，包括 1 例部分缓解和 5 例患者的确认 PSA 反应。3 例 PSA 反应持续时间较长的患者接受了姑息性放疗。需要进一步研究评估该疫苗与其他免疫肿瘤药物和/或姑息性放疗联合应用的临床获益和免疫原性。
试验注册号
NCT03481816。
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