PO.IM01.07 · 免疫学
对适应性细胞和髓系细胞进行体内CAR mRNA工程改造可实现对实体瘤的强效抗肿瘤控制
In vivo CAR mRNA engineering of both adaptive and myeloid cells enables potent anti-tumor control of solid cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：在实体瘤中，嵌合抗原受体（CAR）T细胞疗法因无法克服归巢不良、抗原异质性以及肿瘤微环境（TME）中的免疫抑制性髓系细胞而受到限制。在此，我们提出体内多免疫细胞编程，旨在使用单一工程化产品精确且同时地对多种免疫细胞类型进行编程。该方法建立在体内CAR-mRNA工程化CAR髓系细胞的临床经验之上，后者可营造促炎性肿瘤环境。通过将非靶向和靶向LNP递送、优化的mRNA以及细胞特异性CAR结构相结合，我们赋予髓系细胞、NK细胞和T细胞量身定制的效应功能。
方法：将针对髓系、NK或T细胞信号传导优化的抗HER2 CAR mRNA包裹于LNP中并静脉给药。在携带同基因hHER2-MC38结肠腺癌肿瘤的免疫健全hHER2转基因小鼠中评估抗肿瘤疗效。
结果：在结直肠肿瘤模型中，用CAR mRNA/LNP对髓系细胞和NK细胞进行重编程可驱动肿瘤消退、延长生存期、重塑肿瘤微环境、增强抗原呈递，并增强T细胞浸润和激活。同样，用CAR mRNA/tLNP工程化的T细胞也引发了强劲的抗肿瘤活性。值得注意的是，将细胞特异性CAR mRNA/LNP共递送至髓系和T细胞两个区室产生了更强的肿瘤控制，凸显了协调性多谱系免疫工程的强大力量。
结论：本研究表明，同时用CAR对髓系细胞、T细胞和NK细胞进行体内工程改造，能够协调固有免疫和适应性免疫的协同作用，实现强效抗肿瘤活性。该策略为细胞治疗提供了一种可扩展的现货型方法，并为克服实体瘤的复杂性建立了新的治疗范式。
查看英文原文 English abstract
Background: In solid tumors, chimeric antigen receptor (CAR) T cell therapies are limited by their inability to overcome poor trafficking, antigen heterogeneity and the immunosuppressive myeloid cells in the tumor microenvironment (TME). Here, we introduce in vivo multi-immune cell programming designed to precisely and simultaneously program multiple immune cell types using a single engineered product. This approach builds on the clinical experience with in vivo CAR-mRNA engineered CAR myeloid cells that created a pro-inflammatory tumor environment. Combining non-targeted and targeted LNP delivery, optimized mRNA, and cell-specific CAR architecture, we endow myeloid cells, NK cells and T cells with tailored effector functions.
Methods: Anti-HER2 CAR mRNAs optimised for myeloid, NK or T cell signalling were encapsulated in LNPs and delivered intravenously. Anti-tumor efficacy was evaluated in immunocompetent hHER2 transgenic mice bearing syngeneic hHER2-MC38 colon adenocarcinoma tumors.
Results: In a colorectal tumor model, myeloid- and NK-cell reprogramming with CAR mRNA/LNPs drove tumor regression, prolonged survival, remodeling of the tumor microenvironment, greater antigen presentation, and enhanced T-cell infiltration and activation. Likewise, T cell engineered with CAR mRNA/tLNPs elicited robust anti-tumor activity. Notably, co-delivery of cell-specific CAR mRNA/LNPs to both myeloid and T-cell compartments produced even stronger tumor control, highlighting the power of coordinated multi-lineage immune engineering.
Conclusions: This work demonstrates that simultaneous In vivo engineering of myeloid cells, T cells, and NK cells with CARs can orchestrate the coordinated actions of both innate and adaptive immunity for potent anti-tumor activity. This strategy offers a scalable and off-the-shelf approach for cell therapy and establishes a new therapeutic paradigm for overcoming the complexity of solid tumors.
利益披露 Disclosure
J. Tong,
CREATE Medicines ).
M. Chen,
CREATE Medicines ).
K. Sek,
CREATE Medicines ).
M. Harris,
CREATE Medicines Employment.
J. Chal,
CREATE Medicines Employment.
C. Pouton,
CREATE Medicines ).
A. Johnston,
CREATE Medicines ).
D. Getts,
CREATE Medicines Employment.
R. Hofmeister,
CREATE Medicines Employment.
P. Darcy,
CREATE Medicines ).
J. Ding,
CREATE Medicines Employment.