多功能ferritin纳米颗粒改进肿瘤疫苗对实体瘤治疗效果的研究

Tumor immunotherapy eliminates cancer cells by activating immune cells and has the potential to cure cancer. Therapeutic tumor vaccine induces anti-tumor immune memory and is a research hotspot in tumor immunotherapy. However, due to the insufficient immune activation of tumor vaccine and the immunosuppression of tumor microenvironment, the therapeutic effect of tumor vaccine on solid tumors has not been satisfactory. Nanoparticles are promising drug delivery carriers and vaccine carriers and their application in tumor vaccine is expected to improve the effect of tumor immunotherapy. Using ferritin nanoparticles as a vaccine carrier, we intend to develop a novel DC cell-targeted tumor vaccine by internally wrapping CpG adjuvants and presenting tumor antigens and anti-CD40 antibodies on the surface of ferritin. Meanwhile, by exhibiting tumor-targeting peptide and anti-PD-1 antibody on the surface of ferritin nanoparticles and encapsulating inflammatory inducer CpG in the interior, we plan to achieve tumor-targeted systemic delivery of drugs. The combined use of tumor vaccine and drug delivery carrier has the potential to greatly improve the effectiveness of tumor vaccines in treating solid tumors by activating anti-tumor immune responses, relieving immunosuppression of tumor microenvironment, and inducing tumor internal inflammatory reactions. This project is expected to develop a new type of therapeutic tumor nanovaccine and explores the anti-tumor effects of combination immunotherapy of tumor nanovaccine and immune checkpoint inhibitor, which has great theoretical and clinical applications for tumor immunotherapy.

肿瘤免疫疗法通过活化免疫细胞来清除癌细胞，有可能彻底消灭肿瘤。治疗型肿瘤疫苗诱导抗肿瘤免疫记忆，是肿瘤免疫治疗的研究热点。然而，由于肿瘤疫苗的免疫激活不足和肿瘤微环境的免疫抑制，肿瘤疫苗对实体瘤的治疗效果一直不理想。纳米颗粒是良好的药物递送载体和疫苗载体，将其应用于肿瘤疫苗，有望改进肿瘤免疫治疗效果。该项目以铁蛋白纳米颗粒为载体，内部包裹CpG佐剂，表面展示肿瘤抗原、CD40抗体来制备新型DC细胞靶向性肿瘤疫苗；在铁蛋白表面展示肿瘤靶向肽和PD-1抗体、内部包裹炎症诱导剂CpG，实现肿瘤靶向系统给药；联合使用肿瘤疫苗、药物递送载体，从激活抗肿瘤免疫应答、解除肿瘤免疫抑制、诱导肿瘤内部炎症反应三方面同时作用，有希望极大提高肿瘤疫苗对实体瘤治疗效果。该研究有望开发一种新型治疗型肿瘤疫苗，并探究肿瘤疫苗与免疫筛查点抑制剂联合使用的抗肿瘤效果，对肿瘤免疫治疗具有重要的理论和临床应用价值。

肿瘤免疫疗法靶向机体免疫系统，通过活化免疫细胞来清除癌细胞，并形成免疫记忆来实现长期监视，避免肿瘤复发。纳米颗粒是良好的药物递送载体和疫苗载体，可在肿瘤免疫治疗的多个环节改进治疗效果。该项目利用铁蛋白纳米颗粒作为疫苗载体和药物递送载体的优势，设计肿瘤免疫治疗改进策略，包含三个部分：（1）铁蛋白内部包裹CpG佐剂，表面展示黑色素瘤相关抗原肽并结合CD40抗体来制备新型DC细胞靶向性肿瘤疫苗。本研究构建了铁蛋白表面展示四种黑色素瘤相关抗原肽的AP(4)-rHF、包裹CpG佐剂的AP(4)-rHF-CpG、表面结合CD40抗体的AP(4)-rHF-CpG-CD40纳米颗粒。AP(4)-rHF-CpG可被DC细胞摄取，皮下免疫可快速到达淋巴结，诱导产生抗原特异性抗体，然而只有AP(4)-rHF经皮下免疫小鼠可延缓黑色素瘤生长，CpG和CD40抗体的引入均未提高疫苗效力。AP(4)-rHF纳米颗粒有望开发为黑色素瘤预防性疫苗。（2）在铁蛋白表面展示肿瘤靶向肽RGD并结合PD-1抗体、内部包裹CpG，同时实现抗体和炎症诱导剂的肿瘤靶向系统给药。本研究构建了RGD-rHF-FcBP-PD-1 Ab和RGD-rHF-FcBP-CpG-PD-1 Ab纳米颗粒。RGD-rHF-FcBP-PD-1 Ab经尾静脉注射给药，比同剂量的PD-1抗体单独给药产生更好的抑瘤效果，并且治疗效果优于RGD-rHF-FcBP-CpG-PD-1给药组。研究还发现未融合FcBP的RGD-rHF也可以和PD-1抗体以强亲和力结合，RGD-rHF和PD-1抗体混合给药可以和RGD-rHF-FcBP-PD-1 Ab组产生相同的黑色素瘤抑制效果。RGD-rHF-FcBP或RGD-rHF有望与治疗性PD-1抗体联合使用，促进肿瘤免疫治疗效果。（3）铁蛋白包裹CpG ODN递送给巨噬细胞，诱导巨噬细胞极化为抗瘤型的M1型巨噬细胞。该研究制备了M2型TAM的靶向载体M2pep-rHF，并包裹CpG ODNs制备M2pep-rHF-CpG纳米颗粒。M2pep-rHF-CpG可诱导M2型巨噬细胞极化为M1型巨噬细胞，并抑制4T1肿瘤的生长，有望发展为一种潜在的抗肿瘤治疗药物。该项目探究了几种肿瘤免疫治疗新策略，对肿瘤免疫治疗具有重要的理论和临床应用价值。

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