Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity
Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity
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DOI：
10.1080/2162402x.2015.1074374
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Wang, Lin
中科院分区：
文献类型：
--
作者：
Li, Yongkui;Fang, Min;Wang, Lin
癌症免疫疗法面临的两个主要挑战是相对较低的治疗效果和潜在的副作用。需要新的药物输送系统和有效的药物组合来克服这些挑战。我们利用藻酸盐水凝胶系统局部输送 2 种 FDA 批准的药物，塞来昔布和程序性死亡 1 (PD-1) 单克隆抗体 (mAb)，以治疗荷瘤小鼠。在 B16-F10 黑色素瘤和 4T1 转移性乳腺癌这两种癌症模型中，藻酸盐水凝胶递送系统显着提高了塞来昔布 (CXB)、PD-1 mAb 或两者组合的抗肿瘤活性。这些作用与外周循环和肿瘤区域内药物的持续高浓度有关。引人注目的是，该水凝胶系统同时局部递送塞来昔布和 PD-1 协同增强了肿瘤内和免疫系统中 CD4(+) 干扰素 (IFN)-gamma(+) 和 CD8(+)IFN-gamma(+) T 细胞的存在。这些效应伴随着肿瘤中CD4(+)FoxP3(+)调节性T细胞(Treg)和骨髓源性抑制细胞(MDSC)的减少，反映了免疫抑制反应的减弱。此外，这种组合疗法增加了两种抗血管生成趋化因子 C-X-C 基序配体 (CXCL) 9 和 CXCL10 的表达，并抑制肿瘤内白细胞介素 (IL)-1、IL-6 和环加氧酶-2 (COX2) 的产生，表明促肿瘤血管生成和炎症微环境受到抑制。这种藻酸盐水凝胶介导的塞来昔布和 PD-1 mAb 联合疗法为治疗人类癌症提供了一种潜在的有价值的治疗方案。
Two major challenges facing cancer immunotherapy are the relatively low therapeutic efficacy and the potential side effects. New drug delivery system and efficient drug combination are required to overcome these challenges. We utilize an alginate hydrogel system to locally deliver 2 FDA-approved drugs, celecoxib and programmed death 1 (PD-1) monoclonal antibody (mAb), to treat tumor-bearing mice. In two cancer models, B16-F10 melanoma and 4T1 metastatic breast cancer, the alginate hydrogel delivery system significantly improves the antitumor activities of celecoxib (CXB), PD-1 mAb, or both combined. These effects are associated with the sustained high concentrations of the drugs in peripheral circulation and within tumor regions. Strikingly, the simultaneous dual local delivery of celecoxib and PD-1 from this hydrogel system synergistically enhanced the presence of CD4(+) inteferon (IFN)-gamma(+) and CD8(+)IFN-gamma(+) T cells within the tumor as well as in the immune system. These effects are accompanied with reduced CD4(+)FoxP3(+) regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the tumor, reflecting a weakened immuosuppressive response. Furthermore, this combinatorial therapy increases the expression of two anti-angiogenic chemokines C-X-C motif ligand (CXCL) 9 and CXCL10, and suppresses the intratumoral production of interleukin (IL)-1, IL-6, and cycloxygenase-2 (COX2), suggesting a dampened pro-tumor angiogenic and inflammatory microenvironment. This alginate-hydrogel-mediated, combinatorial therapy of celecoxib and PD-1 mAb provides a potential valuable regimen for treating human cancer.