Chimeric antigen receptor T cell (CAR-T) cell therapy has achieved significant success in treating hematologic malignancies, but its efficacy in solid tumor treatment is relatively limited. Therefore, researchers are exploring other genetically modified immune cells as potential treatment strategies to address the challenges in solid tumor therapy. Chimeric antigen receptor macrophage (CAR-M) involves the genetic engineering of macrophages to express chimeric antigen receptors, enabling them to recognize and attack tumor cells. In contrast to CAR-T cells, CAR-M cells offer distinct advantages such as enhanced infiltration and survival capabilities, along with a diverse array of anti-tumor mechanisms, making them a promising immunotherapy approach that may yield better results in solid tumor treatment. This article provides an overview of the research advancements in CAR-M-mediated tumor immunotherapy, encompassing topics such as the design and transduction of CAR, cell sources, anti-tumor mechanisms and clinical applications. The future research direction in this field will involve leveraging innovative biological technologies to augment the anti-tumor efficacy of CAR-M, understand the underlying mechanisms, and enhance the safety and efficacy of CAR-M therapy.

01 Jan 2025·Journal of Controlled Release

An engineered α1β1 integrin-mediated FcγRI signaling component to control enhanced CAR macrophage activation and phagocytosis

Article

Author: Du, Fuyu ; Jia, Qingan ; Yang, Zuo ; Wang, Zhongliang ; He, Anna ; Yuan, Jingtong ; Ye, Zixuan ; Wang, Huaiyu ; Su, Maozhi ; Yang, Peng ; Ning, Pengbo

Treatment of solid tumors remains difficult, and therefore there has been increased focus on chimeric antigen receptor macrophages (CAR-M) to challenge solid tumors. However, CAR domain design of of adoptive cell therapy, which leads to differences in antitumor activity and triggered antitumor potential, remains poorly understood for macrophages. We developed an α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component for CAR-M specific activation and its antitumor potential. We evaluated CAR-M effects with α1β1 integrin-mediated FcγRI signaling (ACT CAR-M) on the activation and antitumor phagocytic response of macrophages in vitro. Subcutaneous tumor model in BALB/c mice and carcinomatosis model in immunodeficient mice were used to test the antitumor effect of ACT CAR-M compared with CD3ζ CAR-M. The α1β1 integrin-mediated FcγRI signaling engagement of CAR-M was associated with enhanced macrophage activation and specific phagocytosis in primary human macrophages, and significantly improved tumor control and survival in multiple cancer models when compared to CD3ζ CAR-M. RNA-sequencing suggested that α1β1 integrin-mediated FcγRI engagement increased antitumor immunity by enhancing pro-inflammatory M1 phenotype-associated pathways, such as Toll-like receptor signaling, tumor necrosis factor signaling, and IL-17 signaling. α1β1 integrin-mediated FcγRI signaling engagement markedly enhanced antitumor effects of CAR-M immunotherapy, which is proposed as an advanced engineering CAR domain material to expand the clinical application of CAR-M.

01 Jan 2025·Journal of Advanced Research

Exploring CAR-macrophages in non-tumor diseases: Therapeutic potential beyond cancer

Review

Author: Zhu, Mengjuan ; Xin, Qianling ; Luo, Yan ; Chen, Yizhao ; Qiu, Jiaqi ; Wei, Wei ; Li, Ruilin ; Tu, Jiajie

BACKGROUNDAfter significant advancements in tumor treatment, personalized cell therapy based on chimeric antigen receptors (CAR) holds promise for transforming the management of various diseases. CAR-T therapy, the first approved CAR cell therapy product, has demonstrated therapeutic potential in treating infectious diseases, autoimmune disorders, and fibrosis. CAR-macrophages (CAR-Ms) are emerging as a promising approach in CAR immune cell therapy, particularly for solid tumor treatment, highlighting the feasibility of using macrophages to eliminate pathogens and abnormal cells.AIM OF REVIEWThis review summarizes the progress of CAR-M therapy in non-tumor diseases and discusses various CAR intracellular activation domain designs and their potential to optimize therapeutic effects by modulating interactions between cellular components in the tissue microenvironment and CAR-M. Additionally, we discuss the characteristics and advantages of CAR-M therapy compared to traditional medicine and CAR-T/NK therapy, as well as the challenges and prospects for the clinical translation of CAR-M.KEY SCIENTIFIC CONCEPTS OF REVIEWThis review provides a comprehensive understanding of CAR-M for the treatment of non-tumor diseases, analyzes the advantages and characteristics of CAR-M therapy, and highlights the important impact of CAR intracellular domain design on therapeutic efficacy. In addition, the challenges and clinical translation prospects of developing CAR-M as a new cell therapy are discussed.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Discovery	Japan	United Immunity Co. Ltd.Startup	01 Oct 2024

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