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全球临床实验性癌症治疗在70%以上的患者中获得成功
诸平
Credit: Unsplash/CC0 Public Domain
据美国西奈山医院(The Mount Sinai Hospital)2022年12月10日报道,在全球临床试验中,实验性癌症治疗在70%以上的患者中是成功的(Experimental cancer therapy shows success in more than 70% of patients in global clinical trials)。
美国西奈山伊坎医学院蒂施癌症研究所(The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai)的研究人员称,在两项临床试验中,一种能使免疫系统杀死骨髓癌细胞(bone marrow cancer cells)的新疗法成功地治疗了多达73%的患者。
这种被称为双特异性抗体(bispecific antibody)的疗法能同时与T细胞和多发性骨髓瘤细胞(multiple myeloma cells)结合,并引导T细胞即可以用来抵抗疾病的白细胞(white blood cells )杀死多发性骨髓瘤细胞。研究人员将这种策略描述为“让军队直击敌人(bringing your army right to the enemy)”。
现成的免疫疗法—Talquetamab甚至在那些对所有已批准的多发性骨髓瘤疗法都有耐药性的癌症(cancer)患者中也取得了成功。它使用了与其他已批准的疗法不同的靶点:癌细胞表面表达的受体GPRC5D。
Talquetamab在I期和II期试验中进行了测试。在《新英格兰医学杂志》上报道的第一阶段试验确定了两个推荐剂量,并在第二阶段试验中进行了测试。在2022年12月10日举行的美国血液学协会年会(American Society of Hematology annual meeting)上报告了2期试验的结果——Ajai Chari, Monique C. Minnema, Jesus G. Berdeja, Albert Oriol, Niels W.C.J. van de Donk, Paula Rodríguez-Otero, Elham Askari, María-Victoria Mateos, Luciano J. Costa, Jo Caers, Raluca Verona, Suzette Girgis, Shiyi Yang, Rachel B. Goldsmith, Xiang Yao, Kodandaram Pillarisetti, Brandi W. Hilder, Jeffery Russell, Jenna D. Goldberg, Amrita Krishnan. Talquetamab, a T-Cell–Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. New England Journal of Medicine, December 10, 2022. DOI: 10.1056/NEJMoa2204591. https://www.nejm.org/doi/full/10.1056/NEJMoa2204591
参与此项研究的有来自美国纽约西奈山医学(Mount Sinai School of Medicine, New York, USA)、美国莎拉·坎农研究所和田纳西肿瘤学研究所(Sarah Cannon Research Institute and Tennessee Oncology, Nashville, USA)、美国阿拉巴马大学伯明翰分校(University of Alabama at Birmingham, Birmingham, USA )、美国杨森研究与开发(Janssen Research and Development, Spring House; Janssen Research and Development, La Jolla, USA)、美国希望之城综合癌症中心(City of Hope Comprehensive Cancer Center, Duarte, California, USA); 荷兰乌得勒支大学(Utrecht University, Netherlands)、荷兰阿姆斯特丹自由大学(Vrije Universiteit Amsterdam, Netherlands); 西班牙巴塞罗那的加泰罗尼亚肿瘤研究所和约瑟普·卡雷拉斯研究所(Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain)、西班牙潘普洛纳的纳瓦拉大学诊所(Clínica Universidad de Navarra, Pamplona, Spain)、西班牙马德里的吉梅内斯·迪亚兹基金会大学医院(Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain)、西班牙萨拉曼卡大学医院(University Hospital of Salamanca),萨拉曼卡生物医学研究所(Instituto de Investigación Biomédica de Salamanca),癌症研究中心(Centro de Investigación del Cáncer),萨拉曼卡癌症网络生物医学研究中心(Centro de Investigación Biomédica en Red de Cáncer, Salamanca)以及比利时列日大学医疗中心(Centre Hospitalier Universitaire de Liège, Liege, Belgium)的研究人员。
研究的参与患者之前都接受过至少3种不同的治疗,但没有达到持久缓解,这表明Talquetamab可以为难以治疗的多发性骨髓瘤患者带来新的希望。
蒂施癌症研究所多发性骨髓瘤项目临床研究主任、两项研究的主要作者阿贾伊·沙里(Ajai Chari)医学博士说:“这意味着几乎四分之三的这些患者正在重获新生。Talquetamab在接受过大量预处理、复发或难治性多发性骨髓瘤(第二常见的血癌)患者中诱导了显著的疗效。它是首个针对多发性骨髓瘤患者GPRC5d蛋白的双特异性药物。”
几乎所有接受标准疗法的骨髓瘤患者都会持续复发。复发或对所有已批准的多发性骨髓瘤疗法产生耐药性的患者预后较差,因此迫切需要额外的治疗。这项研究是一项旨在检测耐受性和找到安全剂量的早期试验,是满足需求的重要一步。
2018年1月至2021年11月期间,本项1期临床试验在全球多家癌症中心招募了232名患者。患者接受了各种剂量的治疗,静脉注射或皮下注射;未来的研究将侧重于每周或每隔一周皮下注射的剂量。
在美国血液学协会(American Society of Hematology简称ASH)上展示的II期试验验证了I期研究的有效性和安全性。II期试验包括143例每周一次的患者和145例每两周一次的高剂量患者。
阿贾伊·沙里博士说,这两组患者的总体反应率约为73%。除罕见的多发性骨髓瘤患者外,不同亚组的应答率均保持不变,该多发性骨髓瘤也会扩散到器官和软组织。两组中超过30%的患者达到完全缓解(未检测到骨髓瘤特异性标志物)或更好,近60%的患者达到“非常好的部分缓解”或更好(表明癌症已显著减少,但不一定减少到零)。
在两个给药组中,达到可测量缓解的中位时间约为1.2个月,每周一次给药的中位缓解持续时间为9.3个月。研究人员正在继续收集每隔一周接受0.8 mg/kg剂量组以及两个剂量组中完全缓解或更好缓解的患者的缓解持续时间数据。
副作用相对较常见,但通常是轻微的。大约有四分之三的患者会出现细胞因子释放综合症(cytokine release syndrome),这是一系列症状,包括免疫疗法常见的发热。大约60%的人经历了皮肤相关的副作用,如皮疹,大约一半的人味觉改变,大约一半的人指甲异常。研究人员表示,极少数患者(5%~6%)因为副作用而停止使用Talquetamab进行治疗。
阿贾伊·沙里博士解释说,研究中观察到的应答率高于目前大多数可获得的治疗,这表明Talquetamab可能为骨髓瘤患者提供一种可行的治疗选择,提供了延长生命的机会,并从其他新的和未来的治疗方法中受益。
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Treatment options for patients whose blood cancer relapses after CAR-T cell therapy
BACKGROUND
G protein–coupled receptor, family C, group 5, member D (GPRC5D) is an orphan receptor expressed in malignant plasma cells. Talquetamab, a bispecific antibody against CD3 and GPRC5D, redirects T cells to mediate killing of GPRC5D-expressing myeloma cells.
METHODS
In a phase 1 study, we evaluated talquetamab administered intravenously weekly or every other week (in doses from 0.5 to 180 μg per kilogram of body weight) or subcutaneously weekly, every other week, or monthly (5 to 1600 μg per kilogram) in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of six previous lines of therapy) or who could not receive these therapies without unacceptable side effects. The primary end points — the frequency and type of dose-limiting toxic effects (study part 1 only), adverse events, and laboratory abnormalities — were assessed in order to select the recommended doses for a phase 2 study.
RESULTS
At the data-cutoff date, 232 patients had received talquetamab (102 intravenously and 130 subcutaneously). At the two subcutaneous doses recommended for a phase 2 study (405 μg per kilogram weekly [30 patients] and 800 μg per kilogram every other week [44 patients]), common adverse events were cytokine release syndrome (in 77% and 80% of the patients, respectively), skin-related events (in 67% and 70%), and dysgeusia (in 63% and 57%); all but one cytokine release syndrome event were of grade 1 or 2. One dose-limiting toxic effect of grade 3 rash was reported in a patient who had received talquetamab at the 800-μg dose level. At median follow-ups of 11.7 months (in patients who had received talquetamab at the 405-μg dose level) and 4.2 months (in those who had received it at the 800-μg dose level), the percentages of patients with a response were 70% (95% confidence interval [CI], 51 to 85) and 64% (95% CI, 48 to 78), respectively. The median duration of response was 10.2 months and 7.8 months, respectively.
CONCLUSIONS
Cytokine release syndrome, skin-related events, and dysgeusia were common with talquetamab treatment but were primarily low-grade. Talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma. (Funded by Janssen Research and Development; MonumenTAL-1 ClinicalTrials.gov number, NCT03399799. opens in new tab.)
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