ISB 2001 三特异性 T 细胞吸引器显示出强大的肿瘤细胞毒性,并克服了多发性骨髓瘤细胞的免疫逃逸机制

IF 23.5 1区 医学 Q1 ONCOLOGY Nature cancer Pub Date : 2024-09-11 DOI:10.1038/s43018-024-00821-1
Laura Carretero-Iglesia, Olivia J. Hall, Jérémy Berret, Daniela Pais, Carole Estoppey, Myriam Chimen, Thierry Monney, Jeremy Loyau, Cyrille Dreyfus, Julie Macoin, Cynthia Perez, Vinu Menon, Isabelle Gruber, Amélie Laurendon, Lydia N. Caro, Girish S. Gudi, Tomomi Matsuura, Piet H. van der Graaf, Stanislas Blein, M. Lamine Mbow, Rebecca Croasdale-Wood, Ankita Srivastava, Michael R. Dyson, Thomas Matthes, Zeynep Kaya, Claire M. Edwards, James R. Edwards, Sophie Maiga, Catherine Pellat-Deceunynck, Cyrille Touzeau, Philippe Moreau, Cyril Konto, Adam Drake, Eugene A. Zhukovsky, Mario Perro, Maria Pihlgren
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引用次数: 0

摘要

尽管针对单一肿瘤相关抗原的免疫疗法取得了最新进展,但多发性骨髓瘤患者最终还是会复发。ISB 2001 是一种联合靶向 BCMA 和 CD38 的 CD3+ T 细胞吸引剂(TCE),旨在提高对多发性骨髓瘤的细胞毒性。通过单个 TCE 靶向两种肿瘤相关抗原,可在模拟天然肿瘤异质性的 BCMA 和 CD38 肿瘤表达谱的不同范围内产生卓越的细胞毒性效力,提高对竞争性可溶性因子的抵抗力,并在患者来源样本和小鼠模型中表现出卓越的细胞毒性效力。尽管 CD38 在人体组织中广泛表达,但与仅靶向 CD38 的 TCE 相比,ISB 2001 在没有肿瘤细胞的情况下显示出较低的 T 细胞活化谱。为了确定正在进行的临床试验(NCT05862012)的最佳首次用药剂量,我们利用临床前数据开发了一种创新的定量系统药理学模型,采用最小药理活性剂量法,从而减少患者接触次有效剂量疗法的机会。
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ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells
Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3+ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies. Perro and colleagues develop a CD3+ T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma, demonstrate cytotoxicity in patient-derived samples and murine models and develop a quantitative systems pharmacology model.
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来源期刊
Nature cancer
Nature cancer Medicine-Oncology
CiteScore
31.10
自引率
1.80%
发文量
129
期刊介绍: Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.
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