作者: Tomasello, Gianluca ; Celotti, Andrea ; Bonomi, Maria ; Hahne, Jens Claus ; Pagkali, Antonia ; Petrelli, Fausto ; Ghidini, Michele ; Grizzi, Giulia ; Venetis, Kostantinos ; Denaro, Nerina ; Fusco, Nicola

Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell-cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.

2023-04-01·Life Sciences

Current progress and challenges of immunotherapy in gastric cancer: A focus on CAR-T cells therapeutic approach

Review

作者: Abdollahpour-Alitappeh, Meghdad ; Mirzaei, Yousef ; Bagheri, Nader ; Mer, Ali Hussein ; Entezam, Mahshad ; Sanaei, Mohammad-Javad ; Azadegan-Dehkordi, Fatemeh

Gastric cancer (GC) is a severe malignancy, accounting for the third most common cancer death worldwide. Despite the development of chemo-radiation therapy, there has not been sufficient survival advantage in patients with GC who were treated by these methods. GC immunogenicity is hampered by a highly immunosuppressive microenvironment; therefore, further understanding of the molecular biology of GC is the potential to achieve new therapeutic strategies in GC therapy, including specific immunotherapy. Current immunotherapies are mainly based on cytokines, immune checkpoints, monoclonal antibodies (mAb), bispecific antibodies (BisAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR). Immunotherapy has made significant progress in the treatment of GC, so that studies show that nivolumab as a programmed death 1 (PD1) inhibitor has proper safety and effectiveness as a third-line treatment for GC patients. Multiple monoclonal antibodies like ramucirumab and claudiximab were effective in treating GC patients, especially in combination with other treatments. Despite the challenges of CAR therapy in solid tumors, CAR therapy targets various GC cells targets; among them, intercellular adhesion molecule (ICAM)-1 CAR-T cell and CLDN18.2 CAR-T cell have shown promising results. Although responses to all these treatments are encouraging and in some cases, durable, these successes are not seen in all treated patients. The present review represents the development of various immunotherapies especially CAR-T cell therapy, its current use, clinical data in GC, and their limitations.

2022-06-01·Nature Medicine1区 · 医学

Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results

1区 · 医学

Article

作者: Liu, Zhen ; Wang, Yakun ; Li, Jian ; Zhou, Jun ; Peng, Zhi ; Li, Zonghai ; Gao, Huiping ; Gong, Jifang ; Liu, Dan ; Zhang, Miao ; Yuan, Daijing ; Zhang, Xiaotian ; Shen, Lin ; Ma, Hong ; Wang, Wei ; Yuan, Jiajia ; Lu, Ming ; Cao, Yanshuo ; Wang, Huamao ; Xiao, Jun ; Peng, Xiaohui ; Qi, Changsong ; Ge, Sai ; Qin, Yanru ; Wang, Zhenghang ; Lu, Zhihao

AbstractDespite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers (NCT03874897). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 108, 3.75 × 108 or 5.0 × 108 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.

项与 CLDN18.2-targeted CAR-T(仁济医院) 相关的新闻（医药）

2024-07-08

·药时代

一款CAR-T 换 18%股份，信达生物的取舍

在一份由两家公司共同发布的公告披露后，信达生物成为驯鹿生物的战略股东。 2024年7月，两家公司发布公告称，驯鹿生物将按照约定价格购买信达生物BCMA CAR-T产品福可苏®（伊基奥仑赛注射液）的全球市场商业化权益及知识产权许可等权益，并独立负责和决策产品的开发、生产及销售。伊基奥仑赛注射液由信达生物与驯鹿生物合作开发，于2023年6月30日获NMPA批准，在国内正式上市。这个消息意味着，信达生物将完全退出伊基奥仑赛注射液的研发、销售活动，就在这款产品上市一周年之际。同时，根据新闻稿信息，信达生物将此项合作协议金额全部入股驯鹿生物，此后其将持有驯鹿生物18%的股份。官方说法是，基于新的合作框架，双方将就细胞免疫治疗领域达成资源高度整合。 01 是产品不行吗？将伊基奥仑赛注射液从管线剔除后，信达生物的管线中仅存的CAR-T产品就只一款 IBI-345——CLDN18.2 Modular CAR-T，目前处于入I期临床阶段。而正如此前文章中提到过的，就CLDN18.2这个靶点而言，单抗产品目前仅在日本获批上市，预计今年年底将被FDA批准上市。此外，从去年开始包括信达生物在内的几家公司均陆续公布了其CLDN18.2 ADC产品进入III期临床试验的消息。整体而言，靶点赛道竞争相当白热化。伊基奥仑赛注射液是信达生物唯一一个已经上市的CAR-T产品，被NMPA批准用于治疗三线及以上复发/难治性多发性骨髓瘤成人患者。值得注意的是，这也是国内首个获批的靶向BCMA CAR-T产品。目前，伊基奥仑赛注射液关于治疗既往经过1-2线治疗且来那度胺耐药的复发/难治性多发性骨髓瘤患者及自身免疫性疾病方向（难治性重症肌无力）的IND申请已被相关药监部门批准。此外，根据近日驯鹿生物在2024 EHA上的口头报告信息，在一项针对不符合自体干细胞移植条件的高危NDMM患者的I期临床试验中，经伊基奥仑赛注射液治疗后（中位随访时间7.46个月），100%受试者均达到MRD阴性，且有71.4%的受试者维持MRD阴性超过12个月。试验的ORR（客观缓解率）达到100%，并有93.8%达到严格意义的完全缓解。这意味着，伊基奥仑赛注射液在此类患者人群的一线治疗中展现出了极好的前景。从研发情况来看，伊基奥仑赛注射液的早期临床试验正传递出积极信号。 02 困境聚焦商业化正如大家所知悉的，包括伊基奥仑赛注射液在内的一众CAR-T疗法面临的最大困境是商业化难的问题。伊基奥仑赛注射液国内定价一百余万元，单价格就将大部分患者劝退。同时，对于CAR-T这类高价药而言，若想进医保，企业的让步需要很大。据悉，目前进入医保的普通药普遍降价60%左右，按此最保守折扣来看，一款CAR-T若要进入医保企业方也要让步60万元。事实上，参考此前一些高价药进医保的门槛来看，降价60%后的CAR-T也仍需要40余万元，相较于医保内其他产品仍属于高价。但是对企业而言，40万的价格刨去成本后，营收大概率指向负数。据《国际癌症杂志》上的一篇文章，每剂CAR-T的生产材料成本约为4.3万美元（约合人民币31万元）。其中，用于CAR-T转导的慢病毒载体占成本的66%，用于细胞分选过程的磁珠占成本的14.4%。而这才仅是最基本的生产材料，研发投入、失败风险、后期推广等支出并未计算在内。在一众国产CAR-T中，以营收水平来看，目前较成功的是传奇生物的CARVYKTI，上市后的第一个完整年营收达5亿美元，且目前正在高速增长中。据悉，其2024 Q1季度营收达到1.57亿美元。不过这款产品目前尚未在国内获批上市，上市申请于2022年底被CDE承办。目前，多款已在国内上市的CAR-T产品的商业推广也更多集中在创新支付方式上，包括上海、长沙、苏州等多地已将CAR T细胞疗法纳入“惠民宝”等当地定制医疗保险。 03 为何逆行？ CAR-T疗法的市场规模正在高速增长。有机构预测，2024年中国CAR-T疗法需求量将达到1392针，市场规模可达16.4亿元。同时，根据弗若斯特沙利文数据，到2030年这一数字将达到287亿元人民币。事实上，放眼全球，中国企业对于CAR-T疗法的热情也相当显著。截至2023年11月，国内CAR-T细胞疗法的临床研究数量已达655项，位居全球首位。在一众企业还在持续涌入这个赛道的时候，信达却逆行将产品出手，考量是什么？ CAR-T疗法在信达生物的管线中仅占了很小的比例。根据2024年3月这家公司公布的管线更新情况，信达生物仅有两款CAR-T产品，且未有其他类别细胞疗法产品。其中，伊基奥仑赛注射液为与驯鹿生物合作开发，CLDN18.2 CAR-T为与罗氏合作开发。相比于其管线中的玛仕度肽（GLP-1/GCGR ）、替妥尤单抗注射液（眼科领域）、自免领域的IBI112（IL-23p19）以及肿瘤领域的靶向CLDN18.2、HER2、TROP 2的一众ADC、以及KRAS G12C抑制剂等潜力股，这两款CAR-T产品之于信达生物来讲性价比并不算高。当管线优化成为寒冬中大多数药企的选择时，将产品的所有权益均转让给更聚焦这个领域的驯鹿生物，这样的取舍或许也并不难理解。参考资料 1.https://invivo.citeline.com/ 2.各公司官网 3.其他公开资料封面图来源：pixabay 版权声明/免责声明本文为原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 罗氏TIGIT再败肺癌后，决定提前终止这一研究一家CNS领域 biotech 的红与黑 mRNA CAR-T二期临床试验成功，公司股价却暴跌35%！点击这里，发现价值信息！

细胞疗法免疫疗法抗体药物偶联物临床3期上市批准

100 项与 CLDN18.2-targeted CAR-T(仁济医院) 相关的药物交易

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