An innovative plasmacytoid dendritic cell line-based cancer vaccine primes and expands antitumor T-cells in melanoma patients in a first-in-human trial
An innovative plasmacytoid dendritic cell line-based cancer vaccine primes and expands antitumor T-cells in melanoma patients in a first-in-human trial
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DOI：
10.1080/2162402x.2020.1738812
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发表时间：
2020-01-01
期刊：
影响因子：
7.2
通讯作者：
Plumas，Joel
中科院分区：
文献类型：
--
作者：
Charles，Julie;Chaperot，Laurence;Plumas，Joel
免疫检查点抑制剂的疗效已被证明依赖于先前存在的抗肿瘤免疫；因此，它们与癌症疫苗联合是一种有吸引力的治疗方法。浆细胞样树突状细胞(PDC)是强烈的抗肿瘤反应诱导者，是很有前途的疫苗候选细胞。我们开发了一种基于同种异体PDC细胞的癌症疫苗方法，该细胞在临床前研究中起到了非常强大的抗原提呈细胞的作用。在这项Ib期临床试验中，9名转移性IV期黑色素瘤患者接受了多达6000万个装有4种黑色素瘤抗原的照射PDC细胞，每周一次皮下注射。主要终点是安全性和耐受性。该疫苗耐受性良好，没有记录疫苗引发的严重副作用。值得注意的是，对疫苗没有同种异体反应，但在两名患者中观察到循环中抗肿瘤特异性T淋巴细胞的频率显著增加，并伴随着从幼稚表型到记忆表型的转变，从而证明了抗原特异性T细胞的启动。观察到临床活动的迹象，根据IRRC和白癜风皮损，包括四种稳定的疾病。4名患者在48周时仍活着。我们还证明了与单独的多肽负载PDC株相比，多肽负载PDC株与抗PD-1协同作用能在体外促进特异性T细胞的增殖。综上所述，这些临床观察表明，基于PDC系列的疫苗能够激活和扩大癌症患者的抗肿瘤CD8+细胞反应。进一步的试验应该测试这种疫苗与免疫检查点抑制剂的结合。
The efficacy of immune checkpoint inhibitors has been shown to depend on preexisting antitumor immunity; thus, their combination with cancer vaccines is an attractive therapeutic approach. Plasmacytoid dendritic cells (PDC) are strong inducers of antitumor responses and represent promising vaccine candidates. We developed a cancer vaccine approach based on an allogeneic PDC line that functioned as a very potent antigen-presenting cell in pre-clinical studies. In this phase Ib clinical trial, nine patients with metastatic stage IV melanoma received up to 60 million irradiated PDC line cells loaded with 4 melanoma antigens, injected subcutaneously at weekly intervals. The primary endpoints were safety and tolerability. The vaccine was well tolerated and no serious vaccine-induced side effects were recorded. Strikingly, there was no allogeneic response toward the vaccine, but a significant increase in the frequency of circulating anti-tumor specific T lymphocytes was observed in two patients, accompanied by a switch from a naïve to memory phenotype, thus demonstrating priming of antigen-specific T-cells. Signs of clinical activity were observed, including four stable diseases according to IrRC and vitiligoïd lesions. Four patients were still alive at week 48. We also demonstrate the in vitro enhancement of specific T cell expansion induced by the synergistic combination of peptide-loaded PDC line with anti-PD-1, as compared to peptide-loaded PDC line alone. Taken together, these clinical observations demonstrate the ability of the PDC line based-vaccine to prime and expand antitumor CD8+ responses in cancer patients. Further trials should test the combination of this vaccine with immune checkpoint inhibitors.