Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients.
Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients.
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DOI：
10.1080/2162402x.2015.1019197
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发表时间：
2015-08
期刊：
影响因子：
7.2
通讯作者：
de Vries IJ
中科院分区：
文献类型：
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作者：
Bol KF;Figdor CG;Aarntzen EH;Welzen ME;van Rossum MM;Blokx WA;van de Rakt MW;Scharenborg NM;de Boer AJ;Pots JM;Olde Nordkamp MA;van Oorschot TG;Mus RD;Croockewit SA;Jacobs JF;Schuler G;Neyns B;Austyn JM;Punt CJ;Schreibelt G;de Vries IJ
自体树突状细胞（DC）疗法是一种实验性细胞免疫疗法，对晚期黑色素瘤患者安全且具有免疫原性。为了进一步改善治疗反应，我们治疗了15例黑色素瘤患者，用自体单核细胞来源的未成熟DC电穿孔，所述DC用编码CD 40配体（CD 40 L）、CD 70和组成型活性TLR 4（caTLR 4）的mRNA以及编码肿瘤相关抗原（TAA;分别为gp 100或酪氨酸酶）的mRNA。此外，DC用作为对照抗原的钥孔血蓝蛋白（KLH）脉冲。生产这种具有高细胞活力、高表达共刺激分子和MHC I类和II类以及产生IL-12 p70的DC疫苗在所有患者中都是可行的。在无疾病进展的情况下，在6个月和12个月后重复接种周期，包括三次接种，每次接种最多15×106 DC，每两周一次。由于DC上的低CCR 7表达，将mRNA优化的DC结内注射，并诱导针对对照抗原的从头免疫应答。在两名患者的皮肤试验浸润淋巴细胞（SKIL）中检测到对酪氨酸酶的T细胞反应。在基线时具有可评价疾病的8例患者中观察到1例混合肿瘤缓解和2例持久肿瘤稳定。总之，自体mRNA优化的DC可以安全地对转移性黑色素瘤患者进行结内给药，但对酪氨酸酶和gp 100的免疫反应有限。
Autologous dendritic cell (DC) therapy is an experimental cellular immunotherapy that is safe and immunogenic in patients with advanced melanoma. In an attempt to further improve the therapeutic responses, we treated 15 patients with melanoma, with autologous monocyte-derived immature DC electroporated with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively active TLR4 (caTLR4) together with mRNA encoding a tumor-associated antigen (TAA; respectively gp100 or tyrosinase). In addition, DC were pulsed with keyhole limpet hemocyanin (KLH) that served as a control antigen. Production of this DC vaccine with high cellular viability, high expression of co-stimulatory molecules and MHC class I and II and production of IL-12p70, was feasible in all patients. A vaccination cycle consisting of three vaccinations with up to 15×106 DC per vaccination at a biweekly interval, was repeated after 6 and 12 months in the absence of disease progression. mRNA-optimized DC were injected intranodally, because of low CCR7 expression on the DC, and induced de novo immune responses against control antigen. T cell responses against tyrosinase were detected in the skin-test infiltrating lymphocytes (SKIL) of two patients. One mixed tumor response and two durable tumor stabilizations were observed among 8 patients with evaluable disease at baseline. In conclusion, autologous mRNA-optimized DC can be safely administered intranodally to patients with metastatic melanoma but showed limited immunological responses against tyrosinase and gp100.