Schaedler Emmanuelle, Remy-Ziller Christelle, Hortelano Julie, Kehrer Nadine, Claudepierre Marie-Christine, Gatard Tanja, Jakobs Christopher, Préville Xavier, Carpentier Antoine F, Rittner Karola
TRANSGENE S.A., 400 Boulevard Gonthier d'Andernach, Parc d'Innovation, 67405 Illkirch-Graffenstaden, France.
Institut of Molecular Medicine, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Vaccine. 2017 Jan 23;35(4):577-585. doi: 10.1016/j.vaccine.2016.12.020. Epub 2016 Dec 21.
TG4010 is an immunotherapeutic vaccine based on Modified Vaccinia virus Ankara (MVA) encoding the human tumor-associated antigen MUC1 and human IL-2. In combination with first-line standard of care chemotherapy in advanced metastatic non-small-cell lung cancer (NSCLC), repeated subcutaneous injection of TG4010 improved progression-free survival in phase 2b clinical trials. In preclinical tumor models, MVATG9931, the research version of TG4010, conferred antigen-specific responses against the weak antigen human MUC1. The combination of a suboptimal dose of MVATG9931 and the type B TLR9 ligand Litenimod (Li28) markedly increased survival in a subcutaneous RMA-MUC1 tumor model compared to the treatment with MVATG9931 or Li28 alone. The requirements for this protection were (i) de novo synthesis of MUC1, (ii) Li28 delivered several hours after MVATG9931 at the same site, (iii) at least two vaccination cycles, and (iv) implantation of MUC1-positive tumor cells in the vicinity to the vaccination site. Subcutaneously injected MVATG9931 allowed transient local gene expression and induced the local accumulation of MCP-1, RANTES, M-CSF, IL-15/IL-15R and IP-10. After repeated injection, CD4 and CD8 T lymphocytes, B lymphocytes, NK cells, pDCs, neutrophils, and macrophages accumulated around the injection site, local RANTES levels remained high. Delayed injection of Li28 into this environment, led to further accumulation of macrophages, the secretion of IL-18 and IL-1 beta, and an increase of the percentage of activated CD69 NK cell. Combination treatment augmented the number of activated CD86 DCs in the draining lymph nodes and increased the percentage of KLRG1 CD127CD8 T cells at the injection site. In vivo depletion of macrophages around the injection site by Clodronate liposomes reduced local IL-18 levels and diminished survival rates significantly. Thus, sequential administration of MVATG9931 and Li28 improves local innate and adaptive immune defense against tumors, arguing for intratumoral delivery of this peculiar sequential combination therapy.
TG4010是一种基于安卡拉改良痘苗病毒（MVA）的免疫治疗性疫苗，编码人肿瘤相关抗原MUC1和人白细胞介素-2。在晚期转移性非小细胞肺癌（NSCLC）中，与一线标准护理化疗联合使用时，在2b期临床试验中，重复皮下注射TG4010可改善无进展生存期。在临床前肿瘤模型中，TG4010的研究版本MVATG9931可引发针对弱抗原人MUC1的抗原特异性反应。与单独使用MVATG9931或Li28治疗相比，次优剂量的MVATG9931与B型Toll样受体9配体利特莫德（Li28）联合使用，可显著提高皮下RMA-MUC1肿瘤模型的生存率。这种保护作用的条件包括：（i）MUC1的从头合成；（ii）在同一部位，在MVATG9931注射数小时后注射Li28；（iii）至少两个疫苗接种周期；（iv）在接种部位附近植入MUC1阳性肿瘤细胞。皮下注射MVATG9931可实现短暂的局部基因表达，并诱导MCP-1、RANTES、M-CSF、IL-15/IL-15R和IP-10在局部积累。重复注射后，CD4和CD8 T淋巴细胞、B淋巴细胞、NK细胞、浆细胞样树突状细胞、中性粒细胞和巨噬细胞在注射部位周围聚集，局部RANTES水平持续升高。在此环境中延迟注射Li28，会导致巨噬细胞进一步聚集、IL-18和IL-1β分泌增加，以及活化的CD69 NK细胞百分比升高。联合治疗可增加引流淋巴结中活化的CD86树突状细胞数量，并提高注射部位KLRG1 CD127CD8 T细胞的百分比。通过氯膦酸盐脂质体在注射部位周围体内清除巨噬细胞，可降低局部IL-18水平，并显著降低生存率。因此，序贯给予MVATG9931和Li28可改善局部先天性和适应性抗肿瘤免疫防御，支持在肿瘤内递送这种特殊的序贯联合疗法。
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