Adoptive cell therapy (ACT) with antigen-specific T cells is a promising treatment approach for solid cancers. Interleukin-2 (IL-2) has been utilized in boosting the efficacy of ACT. However, the clinical applications of IL-2 in combination with ACT is greatly limited by short exposure and high toxicities. Herein, a complex coacervate was designed to intratumorally deliver IL-2 in a sustained manner and protect against proteolysis. The complex coacervate consisted of fucoidan, a specific IL-2 binding glycosaminoglycan, and poly-l-lysine, a cationic counterpart (FPC²). IL-2-laden FPC² exhibited a preferential bioactivity in ex vivo expansion of CD8⁺T cells over Treg cells. Additionally, FPC² was embedded in pH modulating injectable gel (FPC²-IG) to endure the acidic tumor microenvironment. A single intratumoral administration of FPC²-IG-IL-2 increased expansion of tumor-infiltrating cytotoxic lymphocytes and reduced frequencies of myeloid populations. Notably, the activation and persistency of tumor-reactive T cells were observed only in the tumor site, not in the spleen, confirming a localized effect of FPC²-IG-IL-2. The immune-favorable tumor microenvironment induced by FPC²-IG-IL-2 enabled adoptively transferred TCR-engineered T cells to effectively eradicate tumors. FPC²-IG delivery system is a promising strategy for T-cell-based immunotherapies.

中文翻译：

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使用基于褐藻糖胶的 IL-2 递送微胶囊增强过继性 T 细胞疗法

使用抗原特异性 T 细胞的过继细胞疗法 (ACT) 是一种很有前途的实体癌治疗方法。白细胞介素 2 (IL-2) 已被用于提高 ACT 的功效。然而，IL-2联合ACT的临床应用受到短时间和高毒性的极大限制。在此，复杂的凝聚层被设计成以持续的方式肿瘤内递送 IL-2 并防止蛋白水解。复合凝聚层由岩藻依聚糖（一种特异性结合 IL-2 的糖胺聚糖）和聚赖氨酸（一种阳离子对应物 (FPC ² )）组成。载有 IL-2 的 FPC ^{2在 CD8 +} T 细胞的离体扩增中表现出优于 Treg 细胞的优先生物活性。此外，FPC ²嵌入 pH 调节可注射凝胶 (FPC ² -IG) 中以耐受酸性肿瘤微环境。^{FPC 2} -IG-IL-2的单次瘤内给药增加了肿瘤浸润性细胞毒性淋巴细胞的扩增并降低了骨髓细胞群的频率。值得注意的是，仅在肿瘤部位而非脾脏中观察到肿瘤反应性 T 细胞的激活和持续存在，证实了 FPC ² -IG-IL-2 的局部作用。^{FPC 2} -IG-IL-2诱导的免疫有利肿瘤微环境使过继转移的 TCR 工程 T 细胞能够有效根除肿瘤。FPC ² -IG 递送系统是用于基于 T 细胞的免疫疗法的有前途的策略。