B4M3 CAR-T cell enhance antitumor activity and non-tumor toxicity in ovarian cancer

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-05-24 DOI:10.1016/j.intimp.2025.114919

Feng Ji , Jing Yu , Yuxin Zhu , Hao Lin , Kexing Gao , Mengchen Rao , Yiyang Shan , Sicong Liu , Bo Ding , Yang Shen

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引用次数: 0

Abstract

Chimeric antigen receptor (CAR) T cells have demonstrated promising therapeutic outcomes in hematologic malignancies, but efficacy against most solid tumors, including ovarian cancer (OC). To address CAR-T challenges, we generated CAR-T cells (B4M3 CAR-T) targeting two tumor-associated antigens, B7H3 and MSLN, simultaneously. Immunohistochemistry and proteomics technologies, were employed to analyze the xenograft tumor tissues and key organ tissues at the end of the treatment in vivo assays. B4M3 CAR-T cells demonstrated rapid antitumor effects under in vivo stress conditions, protected against organ damage, and exhibited favorable safety and tolerability. Molecular and signaling studies indicated that B4M3 CAR-T promoted tumor cell death by activating the NF-κB and TNF signaling pathways. Furthermore, B4M3 CAR-T cells enhancing the innate immune response and altering the metabolic profile. Collectively, our study successfully developed B4M3 CAR-T cells, which exhibited significant antitumor effects in ovarian cancer and it provide a novel strategy for the immunotherapy of OC.

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B4M3 CAR-T细胞增强卵巢癌的抗肿瘤活性和非肿瘤毒性

嵌合抗原受体（CAR） T细胞在血液系统恶性肿瘤中的治疗效果很好，但对大多数实体肿瘤，包括卵巢癌（OC）的治疗效果很好。为了应对CAR-T的挑战，我们同时生成了靶向两种肿瘤相关抗原B7H3和MSLN的CAR-T细胞（B4M3 CAR-T）。采用免疫组化和蛋白质组学技术对异种移植瘤组织和治疗结束时的关键器官组织进行体内分析。B4M3 CAR-T细胞在体内应激条件下表现出快速的抗肿瘤作用，保护器官免受损伤，并表现出良好的安全性和耐受性。分子和信号研究表明，B4M3 CAR-T通过激活NF-κB和TNF信号通路促进肿瘤细胞死亡。此外，B4M3 CAR-T细胞增强先天免疫反应并改变代谢谱。总之，我们的研究成功开发了B4M3 CAR-T细胞，该细胞在卵巢癌中表现出显著的抗肿瘤作用，为卵巢癌的免疫治疗提供了一种新的策略。

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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.