A randomized phase II trial of personalized peptide vaccine with low dose cyclophosphamide in biliary tract cancer.
A randomized phase II trial of personalized peptide vaccine with low dose cyclophosphamide in biliary tract cancer.
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DOI：
10.1111/cas.13193
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发表时间：
2017-05
期刊：
影响因子：
5.7
通讯作者：
Yutani S
中科院分区：
文献类型：
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作者：
Shirahama T;Muroya D;Matsueda S;Yamada A;Shichijo S;Naito M;Yamashita T;Sakamoto S;Okuda K;Itoh K;Sasada T;Yutani S
由于晚期胆道癌（aBTC）的预后仍然很差，需要开发新的治疗方法，包括免疫疗法。在目前的研究中，我们进行了一项开放标签随机II期研究，以测试低剂量环磷酰胺（CPA）是否可以改善49例既往治疗过的aBTC患者的抗原特异性免疫反应和个性化肽疫苗（PPV）的临床疗效。对至少一种化疗方案难以耐受的aBTC患者被随机分配接受PPV联合低剂量CPA （100 mg/天，接种前7天）（PPV/CPA, n = 24）或单独PPV （n = 25）。根据预先存在的肽特异性IgG反应，选择最多四种HLA匹配肽，然后皮下给药。在PPV/CPA组中，T细胞对疫苗接种肽的反应往往大于单独PPV组。PPV/CPA组的无进展生存期明显更好(中位时间：6.1个月vs 2.9个月；风险比（HR）： 0.427；P = 0.008)和总生存期（中位时间：12.1个月vs 5.9个月；HR: 0.376; P = 0.004）。PPV单独组，而PPV/CPA组，接种疫苗后血浆IL - 6显著增加，这可能与抑制抗原特异性T细胞反应有关。这些结果表明，低剂量CPA联合治疗可能通过预防IL - 6介导的免疫抑制，为PPV下的aBTC患者提供临床益处。建议进一步的临床研究来阐明PPV/CPA在aBTC患者中的临床疗效。
Since the prognosis of advanced biliary tract cancer (aBTC) still remains very poor, new therapeutic approaches, including immunotherapies, need to be developed. In the current study, we conducted an open‐label randomized phase II study to test whether low dose cyclophosphamide (CPA) could improve antigen‐specific immune responses and clinical efficacy of personalized peptide vaccination (PPV) in 49 previously treated aBTC patients. Patients with aBTC refractory to at least one regimen of chemotherapies were randomly assigned to receive PPV with low dose CPA (100 mg/day for 7 days before vaccination) (PPV/CPA, n = 24) or PPV alone (n = 25). A maximum of four HLA‐matched peptides were selected based on the pre‐existing peptide‐specific IgG responses, followed by subcutaneous administration. T cell responses to the vaccinated peptides in the PPV/CPA arm tended to be greater than those in the PPV alone arm. The PPV/CPA arm showed significantly better progression‐free survival (median time: 6.1 vs 2.9 months; hazard ratio (HR): 0.427; P = 0.008) and overall survival (median time: 12.1 vs 5.9 months; HR: 0.376; P = 0.004), compared to the PPV alone arm. The PPV alone arm, but not the PPV/CPA arm, showed significant increase in plasma IL‐6 after vaccinations, which might be associated with inhibition of antigen‐specific T cell responses. These results suggested that combined treatment with low dose CPA could provide clinical benefits in aBTC patients under PPV, possibly through prevention of IL‐6‐mediated immune suppression. Further clinical studies would be recommended to clarify the clinical efficacy of PPV/CPA in aBTC patients.