Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab
Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab
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DOI：
10.1016/j.jcyt.2016.05.010
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发表时间：
2016-08-01
期刊：
影响因子：
4.5
通讯作者：
Svane, Inge Marie
中科院分区：
文献类型：
--
作者：
Bjoern, Jon;Iversen, Trine Zeeberg;Svane, Inge Marie
背景目标。吲哚胺2，3-双加氧酶(IDO)是一种新兴的肿瘤治疗新靶点，可通过主动免疫治疗(如通过多肽疫苗接种)进行靶向治疗。此外，IDO已被确定为耐受检查点阻断抗体ipilimumab(Ipi)治疗的关键机制。方法：研究方法。10名转移性黑色素瘤患者参加了一项第一阶段的人类临床研究，评估了异丙肾上腺素与IDO合成多肽疫苗IDO联合使用的安全性。二级和三级终点包括疫苗和临床反应。结果。治疗总体上是安全的，耐受性良好。与疫苗相关的不良反应包括疫苗接种部位的I级和II级红斑、水肿和瘙痒，这些反应可以通过轻微的局部皮质类固醇来控制。一名患者出现推测为异丙肾上腺素引起的结肠炎。它最初对大剂量的非肠道皮质类固醇有反应，但后来在患者住进当地医院时复发，在那里他接受了不理想的治疗后死亡。在三名患者中，可在体外检测到疫苗特异性T细胞反应。在最初的评估中，10名接受治疗的患者中有5人病情稳定，其中一人有未经证实的部分反应。结论。IDOLong合成肽疫苗联合异丙肾上腺素治疗一般是安全的，没有增加毒性。该疫苗在一组患者中诱导了容易检测到的T细胞反应。治疗显示出临床活动的迹象，尽管没有超过ipi单独的疗效。结果应该在一项更大的研究中得到证实。
Background aim. Indoleamine 2,3-dioxygenase (IDO) is an emerging new target in cancer therapy that can be targeted with active immunotherapy (e.g. through peptide vaccination). Furthermore, IDO has been identified as a key mechanism underlying resistance to treatment with the checkpoint blocking antibody ipilimumab (ipi). Methods. Ten patients with metastatic melanoma participated in a phase I first-in-human clinical study assessing safety of combining ipi with a 21-mer synthetic peptide vaccine from IDO denoted IDOlong. Secondary and tertiary end points included vaccine and clinical response. Results. Treatment was generally safe and well tolerated. Vaccine related adverse reactions included grade I and II erythema, oedema and pruritus at the vaccination site, which were manageable with mild topical corticosteroids. One patient developed presumed ipi-induced colitis. It initially responded to high-dose parenteral corticosteroids but later relapsed while the patient was admitted to a local hospital, where he died after receiving suboptimal therapy. Vaccine-specific T-cell responses were detectable ex vivo in three patients. At first evaluation, five of the 10 treated patients were in stable disease, one of whom had an unconfirmed partial response. Conclusions. Treatment with IDOlong synthetic peptide vaccine in combination with ipi was generally safe and without augmented toxicity. The vaccine induced readily detectable T-cell responses in a subset of patients. Treatment showed signs of clinical activity, although not exceeding efficacy of ipi alone. Results should be confirmed in a larger study.