fc优化的CD40激动抗体在转移性肿瘤中诱导三级淋巴样结构的形成和全身抗肿瘤免疫

IF 44.5 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-08-14 DOI:10.1016/j.ccell.2025.07.013

Juan C. Osorio, David A. Knorr, Polina Weitzenfeld, Lucas Blanchard, Ning Yao, Maria Baez, Carlo Sevilla, Meghan DiLillo, Jahan Rahman, Ved P. Sharma, Jacqueline Bromberg, Michael A. Postow, Charlotte Ariyan, Mark E. Robson, Jeffrey V. Ravetch

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引用次数: 0

摘要

CD40激动剂增强抗肿瘤免疫，但受全身毒性和疗效差的限制。在这里，我们提出了一项肿瘤内（i.t） 2141-V11的i期研究（NCT04059588），这是一种fc工程抗cd40激动抗体，与抑制受体FcγRIIB结合增强。在12例转移性癌症患者中，2141-V11耐受性良好，无剂量限制性毒性。6名患者经历了肿瘤缩小，包括2名黑色素瘤和乳腺癌患者的完全缓解。2141-V11诱导注射和非注射病变的消退，与完全应答者的全身CD8+ T细胞活化和成熟的三级淋巴样结构（TLSs）相关。在CD40/FcγRs人源化的原位肿瘤小鼠中，i.t 2141-V11促进了TLS的新生形成，促进了独立于淋巴结启动的CD8+ T细胞效应反应。2141-V11介导的体外抗肿瘤作用和持续免疫记忆所产生的局部免疫应答。这些发现表明，i.t 2141-V11是安全的，并促进免疫特权肿瘤微环境，促进全身和持久的抗肿瘤免疫。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer

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Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer

CD40 agonism enhances antitumor immunity but is limited by systemic toxicity and poor efficacy. Here, we present a phase 1 study (NCT04059588) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced binding to the inhibitory receptor FcγRIIB. Among 12 metastatic cancer patients, 2141-V11 was well tolerated without dose-limiting toxicities. Six patients experienced tumor reduction, including two complete responses in melanoma and breast cancer. 2141-V11 induced regression in injected and non-injected lesions, correlating with systemic CD8⁺ T cell activation and mature tertiary lymphoid structures (TLSs) in complete responders. In CD40/FcγRs humanized mice bearing orthotopic tumors, i.t. 2141-V11 promoted de novo TLS formation, facilitating i.t. CD8⁺ T cell effector responses independent of lymph node priming. The resulting local immune responses by 2141-V11 mediated abscopal antitumor effects and sustained immune memory. These findings demonstrate that i.t. 2141-V11 is safe and promotes immune-privileged tumor microenvironments that promote systemic and durable antitumor immunity.

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.