Biomedical Engineering Department, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, China; Peking University International Cancer Institute, Beijing, 100191, China; Peking University-Yunnan Baiyao International Medical Research Center, Beijing, 100191, China.
Biomedical Engineering Department, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, China; Peking University International Cancer Institute, Beijing, 100191, China; Peking University-Yunnan Baiyao International Medical Research Center, Beijing, 100191, China; Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, 100871, China.
Biomaterials. 2025 Jan;312:122740. doi: 10.1016/j.biomaterials.2024.122740. Epub 2024 Jul 31.
Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.
转移是导致肿瘤相关死亡的主要原因。化疗和免疫疗法常用于治疗转移性实体瘤。然而，这些治疗方法与严重的不良反应和预防转移的有限效果有关。在这里，我们报告了一种名为饥饿免疫疗法的新治疗策略，其中将免疫检查点抑制剂与一种超长效 L-天冬酰胺酶联合使用，该酶是一种由 L-天冬酰胺酶（ASNase）和弹性蛋白样多肽（ELP）组成的融合蛋白，称为 ASNase-ELP。ASNase-ELP 的热敏感性使其在肿瘤内注射后能够生成原位储存库，与游离 ASNase 相比，提高了剂量耐受性、改善了药代动力学、持续释放、优化了生物分布，并增强了肿瘤保留。结果，在口腔癌、黑色素瘤和宫颈癌的小鼠模型中，ASNase-ELP 通过选择性和可持续地耗尽肿瘤细胞生存所必需的 L-天冬酰胺，其抗肿瘤功效明显优于 ASNase 或顺铂（一线抗实体瘤药物），且没有观察到任何不良反应。此外，ASNase-ELP 与免疫检查点抑制剂的联合使用在抑制黑色素瘤转移方面比单独使用任何一种疗法都更有效。总的来说，饥饿免疫疗法的协同策略有望重塑难治性转移性肿瘤的治疗格局，并为下一代肿瘤治疗提供新的选择。
