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核心技术专利:CN118964589B侵权必究
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一种 TLR7/8 激动剂与 TGFβ 抑制剂的原位储库,可促进抗肿瘤免疫反应。

An in situ depot for the sustained release of a TLR7/8 agonist in combination with a TGFβ inhibitor promotes anti-tumor immune responses.

机构信息

Department of Health Technology, Biotherapeutic Engineering and Drug Targeting, Technical University of Denmark, Kgs. Lyngby, Denmark.

Animal Health Center Budafok, Budapest, Hungary.

出版信息

Nat Commun. 2024 Sep 3;15(1):7687. doi: 10.1038/s41467-024-50967-w.


DOI:10.1038/s41467-024-50967-w
PMID:39227589
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11371921/
Abstract

Cancer curing immune responses against heterogeneous solid cancers require that a coordinated immune activation is initiated in the antigen avid but immunosuppressive tumor microenvironment (TME). The plastic TME, and the poor systemic tolerability of immune activating drugs are, however, fundamental barriers to generating curative anticancer immune responses. Here, we introduce the CarboCell technology to overcome these barriers by forming an intratumoral sustained drug release depot that provides high payloads of immune stimulatory drugs selectively within the TME. The CarboCell thereby induces a hot spot for immune cell training and polarization and further drives and maintains the tumor-draining lymph nodes in an anticancer and immune activated state. Mechanistically, this transforms cancerous tissues, consequently generating systemic anticancer immunoreactivity. CarboCell can be injected through standard thin-needle technologies and has inherent imaging contrast which secure accurate intratumoral positioning. In particular, here we report the therapeutic performance for a dual-drug CarboCell providing sustained release of a Toll-like receptor 7/8 agonist and a transforming growth factor-β inhibitor in preclinical tumor models in female mice.

摘要

癌症的治愈性免疫反应需要在抗原丰富但免疫抑制的肿瘤微环境(TME)中启动协调的免疫激活。然而,可塑的 TME 和免疫激活药物的全身耐受性差是产生治愈性抗癌免疫反应的根本障碍。在这里,我们引入了 CarboCell 技术,通过在肿瘤内形成持续释放药物的储存库来克服这些障碍,该储存库选择性地在 TME 内提供高载量的免疫刺激药物。CarboCell 因此诱导了免疫细胞训练和极化的热点,并进一步驱动和维持引流肿瘤的淋巴结处于抗癌和免疫激活状态。从机制上讲,这会改变癌变组织,从而产生全身性抗癌免疫反应。CarboCell 可以通过标准的细针技术注射,并且具有内在的成像对比,以确保准确的肿瘤内定位。特别是,在这里我们报告了一种双药物 CarboCell 的治疗性能,该药物提供 Toll 样受体 7/8 激动剂和转化生长因子-β抑制剂的持续释放,用于雌性小鼠的临床前肿瘤模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/394c2d46b8b2/41467_2024_50967_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/4a81d12514dd/41467_2024_50967_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/61191b7b0d95/41467_2024_50967_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/3212194ea98f/41467_2024_50967_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/38c9d399226e/41467_2024_50967_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/394c2d46b8b2/41467_2024_50967_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/4a81d12514dd/41467_2024_50967_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/61191b7b0d95/41467_2024_50967_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/3212194ea98f/41467_2024_50967_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/38c9d399226e/41467_2024_50967_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c6/11371921/394c2d46b8b2/41467_2024_50967_Fig5_HTML.jpg

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本文引用的文献

[1]
Eradication of Staphylococcus aureus in Implant-Associated Osteomyelitis by an Injectable In Situ-Forming Depot Antibiotics Delivery System.

J Infect Dis. 2024-9-23

[2]
Intratumoral delivery of TransCon TLR7/8 Agonist promotes sustained anti-tumor activity and local immune cell activation while minimizing systemic cytokine induction.

Cancer Cell Int. 2022-9-19

[3]
Trial watch: intratumoral immunotherapy.

Oncoimmunology. 2021

[4]
Optical tissue clearing and machine learning can precisely characterize extravasation and blood vessel architecture in brain tumors.

Commun Biol. 2021-7-1

[5]
Delivery routes matter: Safety and efficacy of intratumoral immunotherapy.

Biochim Biophys Acta Rev Cancer. 2021-4

[6]
Intratumoral heterogeneity in cancer progression and response to immunotherapy.

Nat Med. 2021-2

[7]
Tumor repolarization by an advanced liposomal drug delivery system provides a potent new approach for chemo-immunotherapy.

Sci Adv. 2020-9

[8]
Multimodal soft tissue markers for bridging high-resolution diagnostic imaging with therapeutic intervention.

Sci Adv. 2020-8

[9]
Engineered PLGA microparticles for long-term, pulsatile release of STING agonist for cancer immunotherapy.

Sci Transl Med. 2020-8-12

[10]
Assessment of Image-Guided Intratumoral Delivery of Immunotherapeutics in Patients With Cancer.

JAMA Netw Open. 2020-7-1

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