Cbl-b inhibition improves manufacturing efficiency and antitumoral efficacy of anti-CD19 CAR-T cells

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-06 DOI:10.1016/j.intimp.2024.113971

Haoqi Wang , Fei Li , Yuanyuan Feng , Wenqiang Ma , Yuanhao Li , Xueqin Zhao , Jingyi Wu , Chenxi Shi , Lu Zong , Jing Li , Jingjing Cong , Xuefu Wang

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Abstract

Chimeric antigen receptor T (CAR-T) cells represent a promising approach for cancer immunotherapy, yet their efficacy is hindered by immunosuppressive signals in the tumor microenvironment. Casitas B-cell lymphoma protein b (Cbl-b) is a key negative regulator of T cell function. This study investigated whether inhibiting Cbl-b enhances the antitumor activity of human CAR-T cells. The Cbl-b inhibitor NX-1607 was shown to significantly improve CAR-T cell production and function. When applied during the manufacturing phase, NX-1607 increased the yield of anti-CD19 CAR-T cells. Treatment during the expansion phase enhanced cytokine secretion and cytotoxic activity. Notably, continuous NX-1607 treatment throughout manufacturing and expansion maximized CAR-T cell yield, cytokine production, and cytotoxicity. In vivo, NX-1607-treated CAR-T cells exhibited superior efficacy against hematological malignancies. These findings highlight Cbl-b as a therapeutic target for enhancing CAR-T cell manufacturing efficiency and antitumor efficacy, underscoring its potential for clinical applications.

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抑制Cbl-b可提高抗cd19 CAR-T细胞的制造效率和抗肿瘤效果。

嵌合抗原受体T （CAR-T）细胞是一种很有前途的癌症免疫治疗方法，但其疗效受到肿瘤微环境中免疫抑制信号的阻碍。Casitas b细胞淋巴瘤蛋白b （Cbl-b）是T细胞功能的关键负调控因子。本研究探讨抑制Cbl-b是否能增强人CAR-T细胞的抗肿瘤活性。Cbl-b抑制剂NX-1607被证明可以显著改善CAR-T细胞的生成和功能。当在制造阶段使用NX-1607时，可以提高抗cd19 CAR-T细胞的产量。在扩张期处理可增强细胞因子分泌和细胞毒活性。值得注意的是，在整个制造和扩增过程中，连续的NX-1607处理可以最大限度地提高CAR-T细胞的产量、细胞因子的产生和细胞毒性。在体内，nx -1607处理的CAR-T细胞对血液系统恶性肿瘤表现出优越的疗效。这些发现强调了Cbl-b作为提高CAR-T细胞制造效率和抗肿瘤功效的治疗靶点，强调了其临床应用的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.

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