洛克菲勒大学Jeffrey V. Ravetch研究组取得一项新突破。他们揭示了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。2025年8月14日出版的《癌细胞》发表了这项成果。

该团队提出了一项i期研究（NCT04059588）。2141-V11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，2141-V11促进了全新TLS的形成，为i.t提供了便利。CD8⁺ T细胞效应反应独立于淋巴结启动。2141-V11介导的体外抗肿瘤作用和维持免疫记忆的局部免疫应答。这些发现表明，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。

据介绍，CD40激动剂增强抗肿瘤免疫，但受全身毒性和疗效差的限制。

附：英文原文

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

Author: 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

Issue&Volume: 2025-08-14

Abstract: 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.

DOI: 10.1016/j.ccell.2025.07.013

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00319-8