Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study.

IF 10.4 1区生物学 Q1 GENETICS & HEREDITY

Genome Medicine Pub Date : 2024-11-15 DOI:10.1186/s13073-024-01405-5

Tongpeng Xu, Tian Tian, Chen Wang, Xiaofeng Chen, Xiangrong Zuo, Hanyu Zhou, Jianan Bai, Chenhui Zhao, Sujie Fu, Chongqi Sun, Ting Wang, Ling Zhu, Jingzhi Zhang, Enxiu Wang, Ming Sun, Yongqian Shu

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引用次数: 0

Abstract

Background: Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma.

Methods: In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity.

Results: We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME.

Conclusions: Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma.

Trial registration: ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021.

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靶向间皮素的新型多链 DAP-CAR-T 细胞对卵巢癌和间皮瘤的疗效和安全性：一项单臂、开放标签和首次人体试验研究。

背景：尽管在应用嵌合抗原受体（CAR）-T 细胞治疗血液系统恶性肿瘤方面取得了令人瞩目的成就，但它们对实体瘤的疗效仍然差强人意，面临着影响其临床应用的若干挑战。我们之前研究发现，多链DNAX激活蛋白（DAP）CAR结构可提高CAR-T细胞用于实体瘤时的安全性和有效性。特别是，以间皮素（MSLN）为靶点的CAR-T细胞疗法对MSLN阳性实体瘤（包括卵巢癌和间皮瘤）具有治疗潜力：方法：利用体外细胞杀伤试验和异种移植模型确定MSLN靶向DAP-CAR-T细胞和其他CAR-T细胞的抗肿瘤疗效。ELISA和流式细胞术分析用于评估细胞因子的分泌能力和增殖能力。八名有MSLN表达的患者入组，以评估MSLN-DAP CAR-T细胞疗法的安全性和有效性。我们进行了单细胞测序，以探索治疗过程中患者体内免疫细胞的动态变化，并确定与疗效和毒性相关的转录组特征：我们发现，与其他与DAP12、DAP10或CD3Z相关的自然杀伤细胞激活受体相比，由自然杀伤细胞免疫球蛋白样受体截断体和DAP12结合形成的多链DAP-CAR具有更好的细胞毒性和肿瘤杀伤能力。一项单臂、开放标签临床试验（ChiCTR2100046544）评估了MSLN-DAP CAR-T细胞疗法在卵巢癌和间皮瘤患者中的安全性和有效性；2名患者获得部分应答，4名患者病情稳定。此外，单细胞测序分析表明，KT032 CAR-T细胞输注可以招募更多的免疫细胞，暂时重塑TME：我们的研究强调了以MSLN为靶点的多链DAP-CAR-T细胞疗法治疗卵巢癌和间皮瘤患者的安全性和疗效：ChiCTR.org.cn, ChiCTR2100046544 .2021年5月21日

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来源期刊

Genome Medicine GENETICS & HEREDITY-

CiteScore

20.80

自引率

0.80%

发文量

128

审稿时长

6-12 weeks

期刊介绍： Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.