Fc增强型抗CTLA-4、抗PD-1、多柔比星和超声介导的BBB开放:治疗胶质瘤的新型组合免疫疗法。

IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY Neuro-oncology Pub Date : 2024-11-04 DOI:10.1093/neuonc/noae135
Kwang-Soo Kim, Karl Habashy, Andrew Gould, Junfei Zhao, Hinda Najem, Christina Amidei, Ruth Saganty, Víctor A Arrieta, Crismita Dmello, Li Chen, Daniel Y Zhang, Brandyn Castro, Leah Billingham, Daniel Levey, Olivia Huber, Marilyn Marques, David A Savitsky, Benjamin M Morin, Miguel Muzzio, Michael Canney, Craig Horbinski, Peng Zhang, Jason Miska, Surya Padney, Bin Zhang, Raul Rabadan, Joanna J Phillips, Nicholas Butowski, Amy B Heimberger, Jian Hu, Roger Stupp, Dhan Chand, Catalina Lee-Chang, Adam M Sonabend
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引用次数: 0

摘要

背景:胶质母细胞瘤是一种侵袭性极强的脑癌,对传统的免疫疗法策略具有抗药性。Botensilimab是一种Fc增强型抗CTLA-4抗体(FcE-aCTLA-4),在 "冷 "和免疫治疗难治性癌症中显示出持久的活性:方法:我们评估了FcE-aCTLA-4小鼠类似物在治疗难治性胶质母细胞瘤临床前模型中的疗效和免疫微环境表型,既包括单药治疗,也包括与通过低强度脉冲超声和微气泡(LIPU/MB)递送的多柔比星联合治疗。此外,我们还研究了同时接受多柔比星、抗 PD-1 和 LIPU/MB 治疗的 4 例胶质母细胞瘤患者,以探讨多柔比星调节肿瘤相关巨噬细胞/小胶质细胞(TAMs)中 FcγR 表达的新作用:结果:FcE-aCTLA-4与FcγRIV(人类FcγRIIIA的小鼠直向同源物)具有高亲和性结合,FcγRIV在人类胶质母细胞瘤的TAMs中高度表达,在诊断时表达最为活跃。值得注意的是,FcE-aCTLA-4通过TAM介导的吞噬作用,有选择性地消耗瘤内调节性T细胞(Tregs),同时保留外周Tregs。多柔比星是一种具有免疫调节功能的化疗药物,研究发现,在同时接受多柔比星和抗 PD-1 以及 LIPU/MB 的胶质母细胞瘤患者中,多柔比星会上调 TAM 上的 FcγRIIIA 。在免疫治疗耐药的神经胶质瘤小鼠模型中,FcE-aCTLA-4、抗PD-1和多柔比星与LIPU/MB的组合方案达到了90%的治愈率,这与活化的CD8+ T细胞的强健浸润和免疫记忆的建立有关,肿瘤再挑战时的排斥反应证明了这一点:我们的研究结果表明,FcE-aCTLA-4对小鼠胶质瘤具有强大的免疫调节和抗肿瘤作用,当与抗PD-1、多柔比星和LIPU/MB联合使用时,免疫调节和抗肿瘤作用显著增强。我们目前正在一项临床试验(clinicaltrials.gov NCT05864534)中研究这种联合策略。
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Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas.

Background: 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.

Methods: 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).

Results: 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 intratumoral 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.

Conclusions: 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).

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来源期刊
Neuro-oncology
Neuro-oncology 医学-临床神经学
CiteScore
27.20
自引率
6.30%
发文量
1434
审稿时长
3-8 weeks
期刊介绍: Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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