Ionizable Lipid Nanoparticles with Integrated Immune Checkpoint Inhibition for mRNA CAR T Cell Engineering,Advanced Healthcare Materials

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Ionizable Lipid Nanoparticles with Integrated Immune Checkpoint Inhibition for mRNA CAR T Cell Engineering
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2023-08-21 , DOI: 10.1002/adhm.202301515
Alex G Hamilton ₁ , Kelsey L Swingle ₁ , Ryann A Joseph ₁ , David Mai _{1,

2,

3} , Ningqiang Gong ₁ , Margaret M Billingsley ₁ , Mohamad-Gabriel Alameh _{4,

5} , Drew Weissman _{4,

5} , Neil C Sheppard _{2,

3,

6} , Carl H June _{2,

3,

6} , Michael J Mitchell _{1,

2,

5,

7,

8,

9}

Affiliation

The programmed cell death protein 1 (PD-1) signaling pathway is a major source of dampened T cell activity in the tumor microenvironment. While clinical approaches to inhibiting the PD-1 pathway using antibody blockade have been broadly successful, these approaches lead to widespread PD-1 suppression, increasing the risk of autoimmune reactions. This study reports the development of an ionizable lipid nanoparticle (LNP) platform for simultaneous therapeutic gene expression and RNA interference (RNAi)-mediated transient gene knockdown in T cells. In developing this platform, interesting interactions are observed between the two RNA cargoes when co-encapsulated, leading to improved expression and knockdown characteristics compared to delivering either cargo alone. This messenger RNA (mRNA)/small interfering RNA (siRNA) co-delivery platform is adopted to deliver chimeric antigen receptor (CAR) mRNA and siRNA targeting PD-1 to primary human T cells ex vivo and strong CAR expression and PD-1 knockdown are observed without apparent changes to overall T cell activation state. This delivery platform shows great promise for transient immune gene modulation for a number of immunoengineering applications, including the development of improved cancer immunotherapies.

中文翻译：

用于 mRNA CAR T 细胞工程的具有集成免疫检查点抑制功能的可电离脂质纳米颗粒

程序性细胞死亡蛋白 1 (PD-1) 信号通路是肿瘤微环境中 T 细胞活性减弱的主要来源。虽然使用抗体阻断来抑制 PD-1 通路的临床方法已取得广泛成功，但这些方法会导致广泛的 PD-1 抑制，从而增加自身免疫反应的风险。本研究报告了可电离脂质纳米颗粒 (LNP) 平台的开发，该平台可同时实现 T 细胞中治疗性基因表达和 RNA 干扰 (RNAi) 介导的瞬时基因敲除。在开发这个平台的过程中，在共同封装时观察到两种 RNA 货物之间有趣的相互作用，与单独递送任一货物相比，导致表达和敲低特性得到改善。该信使RNA (mRNA)/小干扰RNA (siRNA)共递送平台用于将靶向PD-1的嵌合抗原受体(CAR) mRNA和siRNA离体递送至原代人T细胞，并实现强CAR表达和PD-1敲除观察到整体 T 细胞激活状态没有明显变化。该递送平台为许多免疫工程应用（包括开发改进的癌症免疫疗法）的瞬时免疫基因调节展现了巨大的前景。

更新日期：2023-08-21

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