Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial
Safety and immunogenicity of novel 5T4 viral vectored vaccination regimens in early stage prostate cancer: a phase I clinical trial
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DOI：
10.1136/jitc-2020-000928
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Redchenko, Irina
中科院分区：
文献类型：
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作者：
Cappuccini, Federica;Bryant, Richard;Redchenko, Irina
在过去的二十年里，前列腺癌（PCa）一直在研究作为转移性疾病背景下抗原特异性免疫治疗的靶点，导致2010年第一种治疗性癌症疫苗Sipuleucel-T获得许可。然而，Sipuleucel-T和后来出现的其他实验性PCa疫苗都不能诱导强烈的T细胞免疫。方法在这项首次人体研究中，万斯，我们评估了一种基于两种复制缺陷型病毒，黑猩猩腺病毒（ChAd）和MVA（改良安卡拉牛痘）的新型疫苗接种平台，靶向早期PCa中的癌胚自身抗原5T4。40名新诊断为早期PCa并计划进行根治性前列腺切除术的患者或根据主动监测方案病情稳定的患者被招募到研究中，以评估疫苗安全性和T细胞免疫原性。次要和探索性终点包括前列腺的免疫浸润、前列腺特异性抗原（PSA）变化以及抗原特异性T细胞的表型和功能评估。结果该疫苗具有良好的安全性。通过离体IFN-γ ELISpot在血液中测量疫苗接种诱导的5T4特异性T细胞应答，并在大多数患者中检测到，应答者的平均水平为每百万外周血单核细胞198个斑点形成细胞。流式细胞术分析证明循环中存在CD8+和CD4+多功能5T4特异性T细胞。从治疗后的前列腺组织中分离5T4反应性肿瘤浸润淋巴细胞。一些患者在接种疫苗后2 - 8周出现一过性PSA升高，可能表明靶器官出现炎症反应。结论ChAdOx1-MVA 5T4疫苗在循环中引起的良好安全性和T细胞应答以及在前列腺中检测到的T细胞应答支持在功效试验中评估ChAdOx1-MVA 5T4疫苗。这种疫苗接种策略是否产生足够大的免疫应答以介导临床疗效，以及它是否在晚期PCa环境中有效，作为晚期疾病的单一疗法或作为多模式PCa治疗的一部分，还有待观察。为了解决这些问题，I/II期试验ADVANCE目前正在招募中危PCa患者和晚期转移性去势抵抗性PCa患者，接受这种疫苗与纳武利尤单抗联合治疗。
Background Prostate cancer (PCa) has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for the last two decades leading to a licensure of the first therapeutic cancer vaccine, Sipuleucel-T, in 2010. However, neither Sipuleucel-T nor other experimental PCa vaccines that emerged later induce strong T-cell immunity. Methods In this first-in-man study, VANCE, we evaluated a novel vaccination platform based on two replication-deficient viruses, chimpanzee adenovirus (ChAd) and MVA (Modified Vaccinia Ankara), targeting the oncofetal self-antigen 5T4 in early stage PCa. Forty patients, either newly diagnosed with early-stage PCa and scheduled for radical prostatectomy or patients with stable disease on an active surveillance protocol, were recruited to the study to assess the vaccine safety and T-cell immunogenicity. Secondary and exploratory endpoints included immune infiltration into the prostate, prostate-specific antigen (PSA) change, and assessment of phenotype and functionality of antigen-specific T cells. Results The vaccine had an excellent safety profile. Vaccination-induced 5T4-specific T-cell responses were measured in blood by ex vivo IFN-gamma ELISpot and were detected in the majority of patients with a mean level in responders of 198 spot-forming cells per million peripheral blood mononuclear cells. Flow cytometry analysis demonstrated the presence of both CD8+ and CD4+ polyfunctional 5T4-specific T cells in the circulation. 5T4-reactive tumor-infiltrating lymphocytes were isolated from post-treatment prostate tissue. Some of the patients had a transient PSA rise 2-8 weeks following vaccination, possibly indicating an inflammatory response in the target organ. Conclusions An excellent safety profile and T-cell responses elicited in the circulation and also detected in the prostate gland support the evaluation of the ChAdOx1-MVA 5T4 vaccine in efficacy trials. It remains to be seen if this vaccination strategy generates immune responses of sufficient magnitude to mediate clinical efficacy and whether it can be effective in late-stage PCa settings, as a monotherapy in advanced disease or as part of multi-modality PCa therapy. To address these questions, the phase I/II trial, ADVANCE, is currently recruiting patients with intermediate-risk PCa, and patients with advanced metastatic castration-resistant PCa, to receive this vaccine in combination with nivolumab.