生物材料介导基因修饰T细胞与树突状细胞局部联用协同对抗肿瘤异质性的机制研究

Cancer is a major disease serious impact on human health. Immunotherapy provided us a new possibility for finally conquer cancer. Heterogeneity is a major feature of solid tumor that bring huge difficulties for treatment. Tumor heterogeneity has been the important scientific problems to be solved. Our previous study found that activating the variety of specific immune responses is the critical factor. We will use a new biopolymer to codelivering chimeric antigen receptors T cells (CAR-T) and immature dendritic cells (iDC) directly to the surface of solid tumor. CAR-T will eradicate tumors more effectively, significantly debulk tumors and increase antigen release. Then with the synergy of exogenous iDC，to convert the tumor bed into a self vaccine site, using debris from eradicated tumor cells as the antigen source to activate host endogenous tumor-specific lymphocytes. This“second-wave”response is broader and is produced by a spectrum of T cells that can eliminate tumor variants not recognized by the programmed CAR T cells. We will demonstrate that codelivery of CAR-T and iDC can trigger host antitumor immunity sufficient to clear tumors and eliminate metastases. Our study will provide new ideas and methods for safely and effectively treating solid tumor with immunotherapy.

肿瘤是严重危害人类健康的重大疾病，免疫疗法为我们最终攻克肿瘤提供了新的策略。实体瘤具有显著异质性，给其治疗带来极大困难，一直是该领域有待解决的关键科学问题。我们前期研究发现，有效激活机体多样化的特异性免疫应答是对抗肿瘤异质性的关键。鉴于此，本课题拟采用新型生物材料介导嵌合抗原受体T细胞（CAR-T）与未成熟树突状细胞（iDC）在实体瘤局部联合递送，实现高剂量CAR-T与肿瘤细胞的充分接触，发挥“第一波”特异性杀伤作用，显著减小肿瘤负荷并大量释放肿瘤抗原，同时改变肿瘤抑制性微环境；进而在外源iDC协同下，充分发挥已坏死肿瘤细胞的自身原位疫苗作用，激起“第二波”由内源多样性的细胞毒性T淋巴细胞（CTL）介导的肿瘤杀伤效应，进一步清除CAR靶抗原阴性的肿瘤细胞，对抗肿瘤异质性，防止逃逸，实现联合免疫疗法有效治疗实体瘤并阐明其机制。本研究为实现局部联合免疫疗法安全有效治疗实体瘤提供新的思路与方法。

目前CAR-T对实体瘤的治疗尚未取得实质性突破，其面临的主要挑战是肿瘤异质性和免疫抑制性微环境。在本项目中我们首次成功建立了一种负载CAR-T细胞的抗低氧、缓释IL-15的可注射生物材料，用于瘤内输送CAR-T细胞，对抗肿瘤抑制性微环境，显著提高其抗实体瘤疗效。将该生物材料瘤内输注后，其首先释放外层凝胶中的HEMOXCell（一种新型氧载体材料），改善低氧的肿瘤微环境，随后CAR-T细胞在缓释IL-15的伴随下，从大孔微球中逐渐迁移到肿瘤部位，发挥抗肿瘤作用。同时，我们尝试了采用该新型生物材料介导CAR-T细胞与不成熟DC细胞（iDC）在实体瘤局部联合递送，实现高剂量CAR-T细胞与肿瘤细胞的充分接触，发挥特异性杀伤作用，显著减小肿瘤负荷并大量释放肿瘤抗原；进而在外源iDC协同下，充分发挥已坏死肿瘤细胞“自身”原位疫苗作用，激起由内源多样性的细胞毒性T淋巴细胞介导的肿瘤杀伤效应，进一步清除CAR靶抗原阴性的肿瘤细胞，对抗肿瘤异质性。本项目开发的新型可注射生物材料，具有良好的临床转化应用前景，可作为多种免疫细胞和药物的局部缓释平台，为实现联合免疫疗法安全有效治疗实体瘤提供新的思路和有力保障。