可注射糖肽水凝胶的制备及用于肿瘤联合免疫治疗研究

In recent years, the development of cancer immunotherapy has reached an important inflection point in the history of cancer therapy, which has achieved great progress in the treatment of melanoma and haematological malignancies. However, there are still several critical hurdles that remain before the full clinical potential of tumor immunotherapy can be realized and broadly applied. Established tumors may escape immune detection and eradication after the evolvement in the face of a competent host immune system, during which three characteristic phases of cancer development have been postulated: elimination, equilibrium and escape, teamed as “immuno-editing”. The understanding of inherent immune biology related to cancer is to better define strategies to harness the human immune response against cancer to achieve durable responses and/or complete eradication of cancer in patients safely. Therefore, immunotherapy approaches, which could induce tumor antigen-specific T cell activation and infiltration of cytotoxic T lymphocytes (CTLs) into tumors by promoting tumor specific immune response and disabling immunosuppression in the tumor microenvironment, would be more effective. Herein, a kind of injectable hydrogel is designed based on glycosylated-polypeptides. Firstly, it can be used as three-dimensional matrices to incorporate various combinations of inflammatory cytokines, immune danger signal and tumor specific antigens to control the activation and localization of host DC populations in situ, which is expected to enhance host immunity by maintaining local and systemic CTL responses for extended periods. Secondly, it can also serve as drug repository for controlled release of cytokines and tumor immunosuppression microenvironment inhibitors to facilitate synergistic treatment effects, which interfere with tumor cells, CTLs and immunosuppression cells directly (eg. tumor-associated macrophages, regulatory T lymphocyte, myeloid-derived suppressor cells). This research would provide a novel platform for future effective combinational cancer immunotherapy.

近年来，免疫治疗逐渐成为又一种重要的肿瘤治疗手段，在黑色素瘤和血液学恶性肿瘤的治疗中取得了重要进展。但是，恶性肿瘤的免疫治疗依然存在很多问题，已经形成的肿瘤通过多种宿主、肿瘤和免疫系统间的相互作用，逃脱机体的免疫侦测和清除。因此，促进肿瘤特异性免疫和解除肿瘤驱动性免疫抑制，诱导足够的效应淋巴细胞在肿瘤组织浸润并对抗负调节，是治疗的关键。基于此，本项目拟开发一种可注射糖肽共聚物水凝胶，以此为支架负载肿瘤特异性抗原，皮下接种后原位募集调控抗原递呈细胞，刺激免疫反应，促进原位和系统性效应T细胞的产生；肿瘤原位长效控释细胞因子和肿瘤免疫抑制微环境调控药物，干预肿瘤细胞、效应性T细胞和免疫抑制细胞，实现协同治疗。通过此研究，将为肿瘤联合免疫治疗提供新策略和药物递送平台。

免疫治疗已成为继手术、放疗和化疗之后一种重要的肿瘤治疗手段，在黑色素瘤和血液学恶性肿瘤的治疗中取得了重要进展。促进肿瘤特异性免疫和解除肿瘤驱动性免疫抑制，诱导足够的效应淋巴细胞在肿瘤组织浸润并对抗负调节，是有效治疗的关键。基于此，本项目开发了可注射多肽共聚物水凝胶，系统研究了水凝胶的制备与物理化学性质，以此为支架负载肿瘤特异性抗原，皮下接种后原位募集调控抗原递呈细胞，激活和增强免疫应答，及其肿瘤免疫治疗效果。首先，通过“点击”化学反应，将超亲水两性离子氟-19磁共振成像造影剂用于多肽水凝胶标记，建立了无创、无辐射、无背景信号干扰、无穿透深度限制的精准示踪方法，实现多肽水凝胶降解、代谢和分布的在体定量评价。其次，多肽水凝胶能够有效的负载肿瘤细胞裂解物和Toll样受体-3激动剂，组成多肽水凝胶疫苗制剂，与传统疫苗相比，多肽水凝胶疫苗延长了注射部位的抗原持续时间，促进抗原向淋巴结回流的百分比，有效增强小鼠体内的T细胞免疫应答，从而有效抑制黑色素瘤的生长。进一步，将多肽水凝胶疫苗与免疫检查点抑制剂进行联合，显著降低了调节性T细胞(Tregs)的产生，同时提高了CD8+ T细胞与Tregs的比例。另外，将成胶因子FEFEFKFKK与CD8+ T细胞表位TRP2(LWVFFDYVS)通过二硫键键合(KKEF-TRP2)，开发了抗原表位水凝胶疫苗，研究发现KKEF-TRP2通过促进抗原提呈细胞的摄取和提呈能力，增强了肿瘤内侵润性T淋巴细胞数量，揭示了其抗肿瘤的可能作用机制。总之，该项目研究表明基于水凝胶材料的免疫治疗，制剂制备工艺简单可控，能够显著增强疫苗免疫原性，提高治疗效果，并且与其它肿瘤治疗模式具有潜在的协同性。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。