肿瘤新生抗原纳米载药系统提高乳腺癌个性化免疫治疗效果的研究

The incidence of breast cancer ranks first in females with malignant tumors. Checkpoint blockade immunotherapy provides a new approach for treatment of advanced breast cancer, but many challenges remain to be addressed, such as the low response rate or poor efficacy with single checkpoint inhibitor. In this project, acid-activatable PEGylated (-)-epigallocatechin-3-O-galate (EGCG) and EGCG-neoantigen conjugates will be synthesized. S-aPDL1/Neo@NP, an acid-activatable nanoplatform for personalized immunotherapy, will be prepared via the hydrophobic interaction between the EGCG derivatives and anti-PD-L1 antibody (aPDL1). The nanoplatform improves the stability of neoantiges and prolongs its half-life time in vivo. Moreover, S-aPDL1/Neo@NP could avoid the “on target off tumor” effect of aPDL1, thus reducing the immune related adverse effects. Once accumulating in tumors via EPR effect, the nanoplatform could be activated for releasing drugs, and sequentially prime the antigen specific CTLs and promote its infiltration into solid tumors. The aPDL1 also regulates the immunosuppressive tumor microenvironment by blocking the PD-1/PD-L1 pathway. Finally, the therapeutic benefits of breast cancer could be improved via S-aPDL1/Neo@NP-based personalized immunotherapy. The project is obviously original and innovative, and can lead to significant breakthrough in personalized cancer immunotherapy.

乳腺癌发病率居女性恶性肿瘤发病率首位，目前对中晚期乳腺癌尚缺乏有效治疗策略。免疫检查点阻断疗法为乳腺癌治疗提供了新手段，但仍面临诸多挑战，如响应率低或单独治疗效果不佳等。本项目拟合成pH敏感的表没食子儿茶素没食子酸酯衍生物（PEG-CDM-EGCG）和新生抗原（Neo）键合物（EGCG-Neo），通过与anti-PD-L1抗体（aPDL1）的疏水相互作用，构建一种新型肿瘤微环境pH响应性纳米载药系统（S-aPDL1/Neo@NP）。S-aPDL1/Neo@NP可提高Neo稳定性，延长其体内半衰期，避免aPDL1与正常组织表达的PD-L1结合，减少免疫相关不良反应；经EPR效应富集到肿瘤后，可发生酸解离，释放Neo和aPDL1，激活抗原特异性CTL并促进其瘤内浸润，解除免疫抑制，提高乳腺癌个性化免疫治疗的效果。该项目研究思路新颖，有望在大幅提高乳腺癌个性化免疫治疗效果上取得突破。

肿瘤组织的免疫抑制性微环境严重影响免疫系统的识别、杀伤作用，主要因素包括树突状细胞（DCs）功能弱、免疫检查点抑制和T细胞耗竭等。改善DCs的功能、解除免疫检查点抑制对于提高肿瘤免疫治疗效果至关重要。为激活肿瘤抗原特异性T细胞免疫应答，本项目构建了一种新型纳米载药系统高效递送肿瘤新生抗原，并联合免疫检查点阻断抗体，提高对多种类型肿瘤如4T1乳腺癌、B16-F10黑色素瘤的免疫治疗效果。该纳米载药系统显著提高DCs对抗原多肽的摄取，促进肿瘤新生抗原多肽的溶酶体逃逸和呈递，将熟化DCs的比例提高至2.4倍。该纳米载药系统提高了肿瘤新生抗原多肽在靶部位的蓄积与滞留，显著激活肿瘤特异性T细胞，将抗原表位特异性T细胞的比例提高至8.3倍。此外，该纳米载药系统与Anti-PD1免疫检查点抗体、过继转移的DCs疫苗联用，可进一步显著改善抗肿瘤效果，抑制肿瘤生长并延长荷瘤小鼠生存期。该项目的顺利实施为肿瘤新生抗原多肽的高效递送提供了新方法，为改善肿瘤免疫治疗效果，实现个性化免疫治疗提供了新策略，有一定的临床转化潜力。