Liu Yarong, Xiao Liang, Joo Kye-Il, Hu Biliang, Fang Jinxu, Wang Pin
Mork Family Department of Chemical Engineering and Materials Science, ‡Department of Biomedical Engineering, and §Department of Pharmacology and Pharmaceutical Sciences, University of Southern California , Los Angeles, California 90089, United States.
Biomacromolecules. 2014 Oct 13;15(10):3836-45. doi: 10.1021/bm501166j. Epub 2014 Sep 23.
Attempts to develop cell-based cancer vaccines have shown limited efficacy, partly because transplanted dendritic cells (DCs) do not survive long enough to reach the lymph nodes. The development of biomaterials capable of modulating DCs in situ to enhance antigen uptake and presentation has emerged as a novel method toward developing more efficient cancer vaccines. Here, we propose a two-step hybrid strategy to produce a more robust cell-based cancer vaccine in situ. First, a significant number of DCs are recruited to an injectable thermosensitive mPEG-PLGA hydrogel through sustained release of chemoattractants, in particular, granulocyte-macrophage colony-stimulating factor (GM-CSF). Then, these resident DCs can be loaded with cancer antigens through the use of viral or nonviral vectors. We demonstrate that GM-CSF-releasing mPEG-PLGA hydrogels successfully recruit and house DCs and macrophages, allowing the subsequent introduction of antigens by vectors to activate the resident cells, thus, initiating antigen presentation and triggering immune response. Moreover, this two-step hybrid strategy generates a high level of tumor-specific immunity, as demonstrated in both prophylactic and therapeutic models of murine melanoma. This injectable thermosensitive hydrogel shows great promise as an adjuvant for cancer vaccines, potentially providing a new approach for cell therapies through in situ modulation of cells.
开发基于细胞的癌症疫苗的尝试显示出有限的疗效，部分原因是移植的树突状细胞（DCs）存活时间不够长，无法到达淋巴结。开发能够原位调节DCs以增强抗原摄取和呈递的生物材料已成为开发更有效癌症疫苗的一种新方法。在此，我们提出一种两步混合策略，以原位生产更强效的基于细胞的癌症疫苗。首先，通过持续释放趋化因子，特别是粒细胞-巨噬细胞集落刺激因子（GM-CSF），将大量DCs招募到可注射的热敏性甲氧基聚乙二醇-聚乳酸-羟基乙酸共聚物（mPEG-PLGA）水凝胶中。然后，通过使用病毒或非病毒载体，这些驻留的DCs可以负载癌症抗原。我们证明，释放GM-CSF的mPEG-PLGA水凝胶成功招募并容纳了DCs和巨噬细胞，允许随后通过载体引入抗原以激活驻留细胞，从而启动抗原呈递并触发免疫反应。此外，如在小鼠黑色素瘤的预防和治疗模型中所证明的，这种两步混合策略产生了高水平的肿瘤特异性免疫。这种可注射的热敏水凝胶作为癌症疫苗的佐剂显示出巨大的前景，可能通过原位调节细胞为细胞治疗提供一种新方法。
