A Phase I, Multi Center, Open Label Study of CC-98633, BCMA Targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed and/or Refractory Multiple Myeloma

This is a Phase 1, multicenter, open-label study of CC-98633, BCMA-Targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in participants with relapsed and/or refractory multiple myeloma.
The study will consist of 2 parts: dose-escalation (Part A) and dose-expansion (Part B). The dose-escalation part (Part A) of the study is to evaluate the safety and tolerability of increasing dose levels of CC-98633 to establish a recommended Phase 2 dose RP2D(s); and the dose-expansion part (Part B) of the study is to further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of CC-98633 at the RP2D(s).

开始日期2020-08-18

申办/合作机构

Juno Therapeutics, Inc.

100 项与 CC-98633 相关的临床结果

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100 项与 CC-98633 相关的转化医学

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100 项与 CC-98633 相关的专利（医药）

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项与 CC-98633 相关的文献（医药）

2025-04-01·LEUKEMIA

Phase 1 clinical trial of B-Cell Maturation Antigen (BCMA) NEX-T® Chimeric Antigen Receptor (CAR) T cell therapy CC-98633/BMS-986354 in participants with triple-class exposed multiple myeloma

Article

作者: Varun, Divya ; Burgess, Michael R ; Ly, Thomas ; Thorpe, Jerill ; Costa, Luciano J ; Navarro, Garnet ; Ravi, Gayathri ; Atrash, Shebli ; Mailankody, Sham ; Hege, Kristen ; Kaur, Gurbakhash ; Maier, Alison ; McCarthy, Philip ; Derman, Benjamin ; Kumar, Shaji ; Koegel, Ashley K ; Richard, Shambavi ; Shrestha, Alok ; Kelly, Lisa M ; Liedtke, Michaela ; Bergsagel, P Leif ; Das, Sharmila

Abstract:

BCMA-targeted CAR T-cells transformed the treatment of relapsed and refractory multiple myeloma (RRMM), yet improvements are needed in manufacturing, toxicity and efficacy. We conducted a phase 1 clinical trial of BMS-986354, an autologous BCMA CAR T manufactured using an optimized NEX-T® process, in participants with triple-class exposed, RRMM. The 65 participants had a median of 5 (range 3–13) prior regimens, 39% had cytogenetic high-risk, 91% triple-class refractory, and 43% extra-medullar disease. Part A (dose-escalation) of the study enrolled participants in cohorts receiving 20 (N = 7), 40 (N = 24), or 80 (N = 11)x 106 CAR + T-cells. In part B (expansion), an additional 23 participants were treated at the recommended phase 2 dose, 40 ×106 CAR + T cells. Across dose levels, cytokine release syndrome (CRS) occurred in 82% (2% grade ≥3), neurotoxicity in 8% (2% grade ≥3), and infections in 32% of participants (5% grade ≥ 3). The response rate was 95%, with 46% achieving complete responses. Median progression-free survival was 12.3 months (95% CI 11.3–16). Compared to orvacabtagene autoleucel (same CAR construct, conventional manufacturing), BMS-986354 had higher proportion of T central memory cells, were less differentiated and had enhanced potency and proliferative capacity, supporting the use of NEX-T® in future CAR T development.

2024-09-13·CLINICAL CANCER RESEARCH

Reconstitution of the Multiple Myeloma Microenvironment Following Lymphodepletion with BCMA CAR-T Therapy

Article

作者: Zhang, Chunli ; Wang, Yue ; Ning, Shangyong ; Shang, Yongfeng ; Zhou, Xuehong ; Wang, Ting ; He, Lin ; Sun, Luyang ; Zuo, Xin ; Liu, Hui ; Qin, Sen ; Li, Qinghua ; Yun, Xiaoya ; Zhang, Shuai ; Zheng, Enrun ; Xu, Xiaodong ; Yang, Yazi ; Xiang, Pengyu ; Yang, Mengyu ; Feng, Ru

Abstract:

Purpose::

The purpose of this study was to investigate the remodeling of the multiple myeloma microenvironment after B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T (CAR-T) cell therapy.

Experimental Design::

We performed single-cell RNA sequencing on paired bone marrow specimens (n = 14) from seven patients with multiple myeloma before (i.e., baseline, “day −4”) and after (i.e., “day 28”) lymphodepleted BCMA CAR-T cell therapy.

Results::

Our analysis revealed heterogeneity in gene expression profiles among multiple myeloma cells, even those harboring the same cytogenetic abnormalities. The best overall responses of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8+ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells, enhanced CD8+ effector T-cell cytotoxic activity, and elevated type 1 conventional dendritic cell (DC) antigen presentation ability. DC re-clustering inferred intramedullary-originated type 3 conventional DCs with extramedullary migration. Cell–cell communication network analysis indicated that BCMA CAR-T therapy mitigates BAFF/GALECTIN/MK pathway–mediated immunosuppression and activates MIF pathway–mediated anti–multiple myeloma immunity.

Conclusions::

Our study sheds light on multiple myeloma microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.

2024-03-01·Transplantation and cellular therapy

Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma

Article

作者: Jia, Xuefei ; Hashmi, Hamza ; Raza, Shahzad ; Khouri, Jack ; DeJarnette, Shaun ; Anwer, Faiz ; Abdallah, Al-Ola ; Davis, James A ; Dima, Danai ; Ahmed, Nausheen ; McGuirk, Joseph ; Valent, Jason

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.

项与 CC-98633 相关的新闻（医药）

2024-02-27

·Pharmaceutical Technology

Bristol Myers Squibb acquires RayzeBio for $4.1bn

Through the RayzeBio acquisition, BMS will gain access to an RPT manufacturing facility. Credit: JHVEPhoto / Shutterstock.com. Bristol Myers Squibb (BMS) has announced the conclusion of its acquisition of RayzeBio, a clinical-stage radiopharmaceutical company, for $4.1bn. RayzeBio is now a wholly owned BMS subsidiary. The companies signed an agreement for the acquisition in December 2023 in which BMS would acquire all outstanding shares of RayzeBio. The acquisition introduces a radiopharmaceutical therapeutics (RPTs) pipeline to BMS, including the lead programme, RYZ101 (²²⁵Ac-DOTATATE). This therapy is designed to target somatostatin receptor (SSTR)2, which is overexpressed in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) and extensive stage small cell lung cancer (ES-SCLC). A Phase III clinical trial is currently enrolling subjects to assess RYZ101 in individuals with SSTR-positive GEP-NETs who have previously received treatment with lutetium-177-based somatostatin therapies. See Also: CC-98633 by Bristol-Myers Squibb for Refractory Multiple Myeloma: Likelihood of Approval CC-98633 by Bristol-Myers Squibb for Relapsed Multiple Myeloma: Likelihood of Approval Interim data from the Phase Ib portion of the ACTION-1 clinical trial for RYZ101 have shown encouraging tolerability and efficacy. A Phase Ib trial is also progressing to assess RYZ101 as a first-line treatment for ES-SCLC in combination with standard-of-care therapy. The acquisition also includes an RPT manufacturing facility which will commence operations in the first half of 2024. BMS CEO Chris Boerner stated: “We are excited to complete this transaction, which adds RPTs, one of the fastest-growing new modalities for treating patients with solid tumours. “By strengthening and further diversifying our oncology pipeline beyond I-O, we will unlock exciting opportunities that support BMS’s growth in the back half of the decade and beyond. RayzeBio is a pioneer in the application of this novel modality, and we look forward to working with their talented team to accelerate their preclinical and clinical programmes for the benefit of patients around the world.” The latest deal comes after BMS entered a $674m collaboration with US deep tech company VantAI. The partnership will focus on using VantAI’s generative AI platform to design and develop molecular glues – a small molecule that induces or stabilises interactions between two proteins that would not normally go together.

临床1期临床3期并购

2023-06-26

·智慧芽新药科讯

报告下载｜BCMA抑制剂的管线及专利调研报告

2023年6月25日，智慧芽新药情报库正式发布最新管线及专利调研报告《BCMA抑制剂的管线及专利调研报告》（以下简称“报告”）。报告共分为靶点简介、管线药物、专利分析、总结四部分。在“管线药物”部分，先对“全球管线药物概况’进行了统计，包括靶点、适应症、药物类型、临床试验的国家/地区、研发进度五方面的分布特点，并汇总了在中国开展研究的BCMA靶向药物信息，最后解析了已上市的4款靶向药物。在”专利分析“部分，先统计了全球专利分布特点，后对Top 1 专利申请机构BMS的专利进行了较为详细的分析。报告全文限时免费阅读下载，了解详情请点击下方图片。一、靶点简介1.1靶点的结构与表达B细胞成熟抗原（B cell maturation antigen，BCMA），又称CD269、TNFRSF-17，由2.92-kb TNFRSF17基因编码，该基因由3个外显子和2个内含子组成（图1）[1]。BCMA是一种含有184个氨基酸的20.2-kDa III型跨膜糖蛋白，与其他两个TNFR超家族成员，B细胞激活因子受体（BAFF-R）和TACI（又称CD267），协同调节B细胞的增殖、成熟和存活，以及向浆细胞（plasma cells, PCs）的分化[2-8]。与BAFF-R和TACI不同，BCMA几乎只在浆母细胞(plasmablasts)[9]和PCs[10]上表达。在一些记忆B细胞和浆细胞样树突状细胞上也可微弱检测到[11]。BCMA在幼稚B细胞、造血干细胞中检测不到，在大多数正常非血液组织中也检测不到，除了睾丸、气管和一部分胃肠道等，这些器官由于含有PCs而可以检测到[12]。图1 BCMA基因和蛋白1.2靶点的信号通路BCMA有两个激动剂配体（图2）：增殖诱导配体（APRIL）和B细胞激活因子（BAFF），主要由骨髓基质细胞、破骨细胞和巨噬细胞以旁分泌的方式在骨髓中分泌。APRIL对BCMA的亲和力比BAFF高得多，它也与TACI结合，而BAFF对BAFF-R的选择性更强。随后，异常浆细胞，如多发性骨髓瘤（MM）细胞中的多种生长和存活信号级联被激活，最常见的是通过NF-κβ，导致抗凋亡蛋白的上调和细胞粘附分子、血管生成因子和免疫抑制分子的产生。这些导致MM细胞的存活率增加。膜上的BCMA可被γ-分泌酶切割并以可溶性BCMA（sBCMA）的形式释放到血浆中。sBCMA可以与APRIL和BAFF结合，这可能会干扰BCMA信号通路的激活。在MM患者中，血清APRIL和BAFF水平比健康对照组升高约5倍[13]，并且MM分期越晚期，检测到的配体浓度越高[14]。图2 BCMA的信号通路[1]二、管线药物2.1全球BCMA管线药物概况靶点分布：根据智慧芽新药情报库数据对BCMA靶向药物的具体靶点进行统计，在165款管线药物中，97款为针对BCMA单一抗原的靶向药，占总管线药物的58.8%，其次为BCMA+CD3双特异性靶向药，共22款。适应症布局：由于BCMA高度限制性表达于浆母细胞和PCs，且在MM患者中，BCMA在PCs上过表达，早期研究显示，抗BCMA抗体在体外对MM细胞具有强大的细胞毒性，基于诸如此类的研究，各研发机构纷纷布局MM，导致BCMA靶向药物的适应症分布高度集中，造成资源的浪费。药物类型：目前，多种创新的BCMA靶向治疗方式，包括抗体偶联药物( ADC )、 CAR -T细胞和双特异性T细胞接合器(Bispecific T cell engager, BiTE) (图3 )，正在积极进行临床开发。其中以CAR-T为主，共有91个，占总管线药物的55%。图3 排名前十的药物类型及其药物所属研发阶段的分布临床试验的国家/地区分布（图4）：全球共开展357项关于BCMA药物的临床试验，一些有实力的药企出于未来在多国上市或其他考量，采取国际多中心的临床试验方案。所以按照国家为单位进行统计时，会切割这类试验项目，最终统计得到1192项。这其中有155项在中国开展，位列全球第一（13%）；之后是美国，共开展147（12%）项试验。若不考虑人口基数，则中国BCMA靶向药物的研发竞争性较其他国家激烈，然而一旦有药物在中国上市，其面临的适用人群、市场规模也更大。图4 BCMA药物的全球临床试验国家/地区分布三、专利分析3.1全球BCMA相关专利分布特点的统计结果在智慧芽新药情报库→“专利检索”板块→“靶点”栏，输入关键词“BCMA”，检索后共得到11,676条医药类专利信息，现基于这些信息对全球专利的申请/授权趋势、简单法律状态、国家/地区、治疗领域进行统计。申请/授权趋势：图5，从申请时间维度分析，近20年对于CBMA的专利申请在2020年之前呈增长态势，2020年达到专利申请高峰，为2028项，但2021年有所减少，2022年腰斩。授权率最高峰出现在2015年，为48.7%，专利授权量在2016年达到高峰，为260项（当前暂列第一，因为大部分专利尚处于审查状态），但随后授权量并没有随着申请量的猛增而升高，侧面反应出随着BCMA赛道逐渐拥挤，研发管线间的差异化减弱。（对简单法律状态、国家/地区分布、治疗领域分布的统计请见报告）图5 近20年专利申请/授权趋势（如果2012年专利申请在2014年获得授权，授予的专利将在2012年专利申请中以绿色显示）3.23.Top 1 专利申请机构BMS的专利分析3.2.1 BMS专利统计概况据统计，当前TOP10专利申请机构（图6）依次为Bristol Myers Squibb Co.（881项）、Amgen, Inc.（577项）、Novartis AG （538项）、University of Pennsylvania （300项）等9个外国机构及1个中国机构杭州多禧生物科技有限公司（167项）。其中第三、第四个机构合作最为紧密，涉及的专利多达255项。图6 Top 10 专利申请机构合作概况申请量最高的BMS除独立申请七百多项专利外，另有一百多项与其他机构合作。专利申请时间集中于近10年（图7），2018年达到高峰，为190项，授权量高峰出现在2016年，为27项。图7 BMS近10年BMCA相关专利申请/授权趋势（统计逻辑与图3-1一致）当前BMS共布局8款BCMA靶向药物（图8），包括已获批的Idecabtagene Vicleucel（艾基维仑赛），处于临床2期的Anti-BCMA CAR T-cell Therapy(Juno Therapeutics, Inc.)，处于临床1期的CC-92328、CC-98633、JWCAR-129和临床前的Ispectamab，这些药物的核心专利信息及详细分析请见报告。图8 BMS主要开发靶点四、总结首先，在临床疗效方面，从多个临床试验结果可以看出，无论药物类型是CAR-T、ADC，还是双抗，BCMA靶向药对R/RMM均具有显著的临床疗效。当前已获批的4款药物中Teclistamab、Ciltacabtagene autoleucel、Idecabtagene Vicleucel均获得过FDA“突破性疗法“的认定，Belantamab mafodotin被FDA纳入“加速批准”程序，表明BCMA的这条信号通路不仅跟疾病相关，跟同适应症药物相比更具“优效性”。但当前有关BCMA靶向药物的开发，其药物类型、适应症高度集中于CAR-T、MM，机构间重叠度高，赛道竞争较为激烈。点击图片，直达获取报告全文 👇👇👇 参考文献：1.Yu B, Jiang T, Liu D. BCMA-targeted immunotherapy for multiple myeloma. J Hematol Oncol. 2020 Sep 17;13(1):125. doi: 10.1186/s13045-020-00962-7. PMID: 32943087; PMCID: PMC7499842. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499842/pdf/13045_2020_Article_962.pdf2.Coquery CM, Erickson LD. Regulatory roles of the tumor necrosis factor receptor BCMA. Crit Rev Immunol. 2012;32(4):287–305.3.Marsters SA, et al. Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI. Curr Biol. 2000;10(13):785–8.4.Gross JA, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000;404(6781):995–9.5.Thompson JS, et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. J Exp Med. 2000;192(1):129–35.6.Sasaki Y, et al. TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology. J Immunol. 2004;173(4):2245–52.7.Seshasayee D, et al. Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity. 2003;18(2):279–88.8.Darce JR, et al. Divergent effects of BAFF on human memory B cell differentiation into Ig-secreting cells. J Immunol. 2007;178(9):5612–22.9.Avery DT, et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin Invest. 2003; 112(2):286–97.10.O'Connor BP, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199(1):91–8.11.Tai YT, et al. Novel anti-B-cell maturation antigen antibodydrug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123(20):3128–38.12.Carpenter RO, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013;19(8):2048–60.13.Moreaux J, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103(8):3148–57.14.Pan J, et al. Characteristics of BAFF and APRIL factor expression in multiple myeloma and clinical significance. Oncol Lett. 2017;14(3):2657–62.版权声明：本报告版权由智慧芽所有，未经智慧芽授权不得转载、摘编或利用其它方式使用。已获授权的应在授权范围内使用，并注明来源，违反上述声明者，智慧芽将追究其相关法律责任。授权相关事宜请联系：phs@patsnap.com

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100 项与 CC-98633 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
复发性多发性骨髓瘤	临床1期	美国	Juno Therapeutics, Inc.	2020-08-18

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04394650 (ASH 12022 \| ASH 22022) 人工标引	临床1期	复发性多发性骨髓瘤	54	CC 98633	繭觸窪鬱願齋構糧夢鑰(齋範顧艱繭齋鏇窪網蓋) = 膚壓襯糧積鑰夢淵鏇齋糧願憲餘範選鹹構淵積 (構淵鏇廠夢鹽鑰夢鏇構 ) 更多	积极	2022-11-15