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理想情况下，局部免疫治疗既可激发人体针对肿瘤的免疫反应，又能避免全身免疫治疗带来的毒性反应，尤其对于缺乏靶向治疗方法的三阴性乳腺癌。不过，现有的肿瘤基因细胞因子靶向给药策略，受到诸如脱靶或抗载体免疫等不利影响的限制，难以实现局部治疗。自从德国生物新技术公司和美国辉瑞公司、莫德纳公司的新冠疫苗问世以来，信使核糖核酸（mRNA）迅速出圈，成为大众耳熟能详的黑科技，也引起了法国赛诺菲公司等疫苗和肿瘤制药巨头的注意。 2021年9月8日，美国科学促进会《科学》旗下《转化医学》在线发表德国生物新技术公司、美因茨大学医学中心、赛诺菲美国剑桥研发中心的研究报告，探讨了利用细胞因子编码mRNA联合抗肿瘤免疫治疗药物对三阴性乳腺癌等恶性肿瘤进行局部治疗。 该研究首先确定4种可使不同肿瘤消退的细胞因子：白细胞介素IL-12单链、干扰素IFN-α、粒细胞和巨噬细胞集落刺激因子、白细胞介素IL-15寿司状结构域，这些细胞因子的有效抗肿瘤活性依赖于多种免疫细胞群，并且伴有肿瘤内干扰素IFN-γ产生、全身抗原特异性T淋巴细胞扩增、颗粒酶B淋巴细胞＋T淋巴细胞浸润增加、免疫记忆形成。 随后，将编码细胞因子的mRNA溶解于生理盐水，局部注射入不同类型的小鼠肿瘤模型（胰腺癌PAN02、三阴性乳腺癌EMT6、淋巴瘤A20、肝癌HEPA1-6和H22、前列腺癌RM-1、皮肤黑色素瘤B16BL6、肺癌LL2、肾癌RENCA）。 结果发现，该mRNA的抗肿瘤活性不仅超出局部注射的病变范围，并且可抑制远处肿瘤和播散肿瘤的生长。将该mRNA联合免疫細胞程序性死亡受体PD-1抗体，可增强被注射肿瘤和未注射肿瘤的抗肿瘤反应，从而显著提高生存率、加速肿瘤消退。 因此，该临床前研究结果表明，局部注射抗肿瘤细胞因子编码mRNA可促进多种临床前肿瘤模型的抗肿瘤免疫和肿瘤清除，故已进一步开展人体临床研究进行验证。 Sci Transl Med. 2021 Sep 8;13(610):eabc7804.
Local delivery of mRNA-encoding cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models. Christian Hotz, Timothy R. Wagenaar, Friederike Gieseke, Dinesh S. Bangari, Michelle Callahan, Hui Cao, Jan Diekmann, Mustafa Diken, Christian Grunwitz, Andy Hebert, Karl Hsu, Marie Bernardo, Katalin Karikó, Sebastian Kreiter, Andreas N. Kuhn, Mikhail Levit, Natalia Malkova, Serena Masciari, Jack Pollard, Hui Qu, Sue Ryan, Abderaouf Selmi, Julia Schlereth, Kuldeep Singh, Fangxian Sun, Bodo Tillmann, Tatiana Tolstykh, William Weber, Lena Wicke, Sonja Witzel, Qunyan Yu, Yu-An Zhang, Gang Zheng, Joanne Lager, Gary J. Nabel, Ugur Sahin, Dmitri Wiederschain. BioNTech, Mainz, Germany; Sanofi, Cambridge, MA, USA; Johannes Gutenberg University, Mainz, Germany. Encoding antitumor immunity: Cytokine-based treatments for cancer have been hindered by both off-target toxicity and difficulty in achieving local delivery. To address these challenges, Hotz et al. developed a saline-formulated mixture of four mRNAs delivered by intratumoral injection. The mRNAs encoded interleukin-12 (IL-12) single chain, interferon-α, granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. The combination led to robust antitumor immune responses and tumor regression in multiple mouse models, including models with more than one tumor. Together, these data support further development of cytokine-encoding mRNAs as a treatment for cancer. 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. DOI: 10.1126/scitranslmed.abc7804 
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