胶质母细胞瘤是一种高度侵袭性的脑癌，对传统的免疫治疗策略具有抵抗力。 Botensilimab 是一种 Fc 增强型抗 CTLA-4 抗体 (FcE-aCTLA-4)，在“感冒”癌症和免疫治疗难治性癌症中显示出持久的活性。我们评估了 FcE-aCTLA 小鼠类似物的功效和免疫微环境表型在难治性胶质母细胞瘤临床前模型中，无论是作为单一疗法还是与通过低强度脉冲超声和微泡 (LIPU/MB) 输送的阿霉素联合使用，均为 -4。此外，我们研究了 4 名接受阿霉素、抗 PD-1 联合 LIPU/MB 治疗的胶质母细胞瘤患者，以研究阿霉素调节肿瘤相关巨噬细胞/小胶质细胞 (TAM) 中 FcγR 表达的新作用。FcE-aCTLA-4 表现出高亲和力与 FcγRIV 结合，FcγRIV 是人 FcγRIIIA 的小鼠直系同源物，在人胶质母细胞瘤的 TAM 中高度表达，在诊断时表达最为强烈。值得注意的是，FcE-aCTLA-4 通过 TAM 介导的吞噬作用介导肿瘤内调节性 T 细胞 (Treg) 的选择性耗竭，同时保留外周 T 细胞。阿霉素是一种具有免疫调节功能的化疗药物，在接受阿霉素和抗 PD-1 联合 LIPU/MB 治疗的胶质母细胞瘤患者中，发现其 TAM 上的 FcγRIIIA 上调。在免疫治疗耐药性神经胶质瘤的小鼠模型中，FcE-aCTLA-4、抗 PD-1 和多柔比星与 LIPU/MB 的组合方案实现了 90% 的治愈率，这与活化的 CD8 T 细胞的强劲浸润和肿瘤再攻击时的排斥反应证明了免疫记忆的建立。我们的研究结果表明，FcE-aCTLA-4 可在小鼠神经胶质瘤中促进强大的免疫调节和抗肿瘤作用，并且在与抗 PD-1、阿霉素和 LIPU 联合使用时显着增强。 MB。我们目前正在临床试验中研究这种组合策略 (clinicaltrials.gov NCT05864534)。© 作者 2024。由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限都可以通过我们网站文章页面上的权限链接通过我们的 RightsLink 服务获得 - 如需了解更多信息，请联系journals.permissions@oup.com。

Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers.We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor associated macrophages/microglia (TAMs).FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4 mediated selective depletion of intra-tumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge.Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.