Combined vaccine+axitinib therapy yields superior antitumor efficacy in a murine melanoma model.
Combined vaccine+axitinib therapy yields superior antitumor efficacy in a murine melanoma model.
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DOI：
10.1097/cmr.0b013e3283538293
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发表时间：
2012-06
影响因子：
2.2
通讯作者：
Storkus WJ
中科院分区：
文献类型：
--
作者：
Bose A;Lowe DB;Rao A;Storkus WJ
阿昔替尼是一种血管内皮生长因子受体的酪氨酸激酶抑制剂（TKI），在晚期黑色素瘤的背景下作为单一药物应用时，已证明具有适度的疗效。基于所报道的阿西替尼使肿瘤血管“正常化”的能力，我们假设采用阿西替尼加基于特异性肽的疫苗接种的联合治疗将促进保护性T细胞的上级活化和募集到黑色素瘤微环境中，导致增强的治疗益处。使用s.c. M05（B16.0VA）黑色素瘤模型中，我们观察到由7天疗程的阿昔替尼（0.5mg/天口服提供）与皮下注射阿昔替尼（0.5mg/天口服提供）组合组成的治疗方案，疫苗（经腺病毒工程化以产生IL-12 p70的OVA肽脉冲的同基因树突状细胞（DC））与接受任一单一模式治疗的动物相比，产生了针对黑素瘤生长的上级保护并延长了总存活。治疗获益与以下因素相关：i.）肿瘤中抑制细胞（髓源性抑制细胞（MDSC）和Treg）群体的减少，ii.）肿瘤血管内皮细胞的活化，和iii.）1型疫苗诱导的CD 8 + T细胞活化和募集到肿瘤中。这些结果支持联合疫苗+阿西替尼免疫疗法的治疗优势，以及将此类方法转化为临床治疗晚期黑色素瘤患者。
Axitinib, a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors has demonstrated modest efficacy when applied as a single agent in the setting of advanced-stage melanoma. Based on the reported ability of axitinib to “normalize” the tumor vasculature, we hypothesize that combination therapy employing axitinib plus specific peptide-based vaccination would promote superior activation and recruitment of protective T cells into the melanoma microenvironment, leading to enhanced treatment benefit. Using a s.c. M05 (B16.OVA) melanoma model, we observed that a treatment regimen consisting of a 7 day course of axitinib (0.5 mg/day provided orally) combined with a s.c. vaccine (OVA peptide-pulsed syngenic dendritic cells (DC) adenovirally-engineered to produce IL-12p70) yielded superior protection against melanoma growth and extended overall survival when compared to animals receiving either single modality therapy. Treatment benefits were associated with: i.) a reduction in suppressor cell (myeloid-derived suppressor cells (MDSC) and Treg) populations in the tumor, ii.) activation of tumor vascular endothelial cells, and iii.) activation and recruitment of Type-1, vaccine-induced CD8+ T cells into tumors. These results support the therapeutic superiority of combined vaccine + axitinib immunotherapy and the translation of such approaches into the clinic for the treatment of patients with advanced-stage melanoma.