可注射温敏多肽水凝胶用于肿瘤免疫治疗

Immunotherapy is a promising strategy to combat cancer. However, tumor cells can evade the immune response by several pathways, including the release of inhibitory cytokines and metabolites in tumour microenvironments, and the presence of immune checkpoint receptors on effector T-cells. And the short duration period of therapeutic cytokines such as IL-2 and the following weak immune response also contribute to the low immunotherapy efficiency. Immunotherapy based on the injection of immunocytes such as CAR-T and DCs suffers from low cell viability upon injection, short duration in vivo and untargeted cytotoxicity, which all restrict the therapy outcomes. Herein, injectable hydrogels assembled by thermosensitive poly(ethylene glycol)-polypeptide copolymers will be developed to deliver cytokines and drugs or antibodies tailoring the immune inhibitory tumour microenvironments, as well as to play a role as a scaffold for 3D culture of immunocytes. The effect of polypeptide chain length, composition, side-chain modification and conformation change of peptide on the sol-to-gel transition behavior will be demonstrated. The combination therapy strategy is expected to improve the body immunity and decrease the immune inhibitation in tumor microenvironment, resulting in improved antitumor effect. The obtained hydrogels will act as an effective carriers for controlled release of therapeutic cytokines and drugs or antibodies to prolong their in vivo duration period. The subcutaneous injection of cell-loaded hydrogel will maintain the bioactivity of encapsulated cells such as antigen-treated DCs or TILs and provide a suitable environment for cell proliferation. The antitumor efficiency of obtained hydrogel vaccines will be examined and the potential mechanism will be also indicated. All these studies will help to develop a new strategy and vaccine vectors for cancer immunotherapy.

免疫治疗是对抗癌症的一种很有前景的手段。然而，肿瘤细胞会依靠免疫抑制性肿瘤微环境躲避免疫系统。如何有效地降低此现象，同时解决细胞因子或免疫细胞治疗存在的因子或细胞体内存留时间短、细胞存活率低等缺陷引起的免疫应答时间短、强度低是提高肿瘤免疫治疗效果的有效策略。我们拟构建可注射温敏聚乙二醇-多肽共聚物水凝胶，首先阐明多肽的链段长度、组成、侧链修饰，构象变化等对水凝胶性质的影响。以水凝胶为载体递送细胞因子和调控免疫抑制性肿瘤微环境的药物或抗体，进行肿瘤联合免疫治疗，提高机体自身免疫力的同时，抑制免疫抑制性肿瘤微环境的形成。以水凝胶为DCs疫苗的递送佐剂与肿瘤浸润性T细胞（TILs）的三维培养支架，体内原位皮下注射，提高免疫细胞的体内数量与活性，然后联合调控免疫抑制性微环境，提高体内抗肿瘤效果，阐明免疫途径与机制。这些研究将为肿瘤免疫治疗提供新策略与合适的疫苗递送载体。

免疫治疗正在变革癌症治疗。与传统治疗手段，如化疗、放疗相比，其特异性强、毒副作用低。疫苗接种可以激活机体自身的免疫反应清除癌细胞，是一种常用的免疫治疗手段。项目开发了以多肽水凝胶为载体的肿瘤疫苗递送，系统研究水凝胶的制备与物理化学性质和新型疫苗促进树突状细胞成熟，激活T细胞免疫反应，及其肿瘤免疫治疗效果。聚乙二醇-聚肽水凝胶能够高效负载由全细胞裂解物和TLR激动剂组成的肿瘤疫苗，与传统疫苗相比，显著提高树突状细胞成熟，激活更强的抗肿瘤T细胞反应，从而有效抑制黑色素瘤生长。与免疫检查点抑制剂，如anti-PD-1和anti-CTLA-4抗体联合给药，可以显著降低抗体毒性，增强效应CD8 T细胞活性，提高脾脏和瘤内浸润性T细胞的比例，降低调节性T细胞数量。以小分子多肽水凝胶为载体实施过继免疫细胞治疗，结果表明RADA16水凝胶明显提高了树突状细胞疫苗的体内存活率和淋巴结回流效率，及其体内存留时间，从而引起更高水平的T细胞反应，产生良好的肿瘤预防和治疗效果。另外，联合治疗模式，包括低剂量化疗与纳米佐剂，以及光动力治疗和免疫检查点阻断，通过提高肿瘤抗原表达和T细胞识别，协同放大抗肿瘤免疫反应，更有力地抑制恶性肿瘤生长，甚至清除已生长的肿瘤。总之，该项目研究表明基于水凝胶材料的免疫治疗能够显著增强疫苗免疫原性，提高治疗效果，并且与其它肿瘤模式具有优越的协同性。因此，可注射多肽水凝胶为肿瘤免疫治疗提供了新方法，具有良好的临床转化前景。