Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or antivector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin-12 (IL-12) single chain, interferon-α (IFN-α), granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective antitumor activity of these cytokines relied on multiple immune cell populations and was accompanied by intratumoral IFN-γ induction, systemic antigen-specific T cell expansion, increased granzyme B⁺ T cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of distant tumors and disseminated tumors. Combining the mRNAs with immunomodulatory antibodies enhanced antitumor responses in both injected and uninjected tumors, thus improving survival and tumor regression. Consequently, clinical testing of this cytokine-encoding mRNA mixture is now underway.

中文翻译：

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mRNA编码细胞因子的局部递送促进多个临床前肿瘤模型的抗肿瘤免疫和肿瘤根除

局部免疫疗法理想地刺激针对肿瘤的免疫反应，同时避免与全身给药相关的毒性。然而，目前用于肿瘤靶向、基于基因的递送策略受到诸如脱靶或抗载体免疫等副作用的限制。我们研究了生理盐水配制的信使 (m) RNA 的瘤内给药，该信使 (m) RNA 编码四种细胞因子，这些细胞因子被确定为跨不同肿瘤模型的肿瘤消退介质：白细胞介素-12 (IL-12) 单链、干扰素-α (IFN-α)、粒细胞 - 巨噬细胞集落刺激因子和 IL-15 寿司。这些细胞因子的有效抗肿瘤活性依赖于多个免疫细胞群，并伴有肿瘤内 IFN-γ 诱导、全身抗原特异性 T 细胞扩增、颗粒酶 B ^+增加T细胞浸润，形成免疫记忆。抗肿瘤活性超出了治疗的病变范围，并抑制了远处肿瘤和播散性肿瘤的生长。将 mRNA 与免疫调节抗体结合可增强注射和未注射肿瘤的抗肿瘤反应，从而提高存活率和肿瘤消退。因此，目前正在对这种编码细胞因子的 mRNA 混合物进行临床测试。