A Phase 1, Multicenter, Open-Label Study of CB-010, a CRISPR-Edited Allogeneic Anti-CD19 CAR-T Cell Therapy in Patients With Relapsed/Refractory B Cell Non-Hodgkin Lymphoma (ANTLER)

CB010A is a study evaluating safety, emerging efficacy, pharmacokinetics and immunogenicity of CB-010 in adults with relapsed/refractory B cell non-Hodgkin lymphoma after lymphodepletion consisting of cyclophosphamide and fludarabine.

开始日期2021-05-26

申办/合作机构

Caribou Biosciences, Inc.

100 项与 CB-010 相关的临床结果

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100 项与 CB-010 相关的转化医学

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100 项与 CB-010 相关的专利（医药）

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项与 CB-010 相关的文献（医药）

2023-07-01·Cytotherapy

Allogeneic chimeric antigen receptor-T cells with CRISPR-disrupted programmed death-1 checkpoint exhibit enhanced functional fitness.

Article

作者: Fowler, Tristan W. ; Williams, Carolyn ; van Overbeek, Megan ; Bryan, Mara ; Lau, Elaine ; Skoble, Justin ; Kwong, George ; Kohrs, Bryan ; Garner, Elizabeth ; Smith, Stephen C. ; Clarke, Starlynn C. ; McCawley, Shannon ; Fuller, Chris K. ; Sun, Bee-Chun ; Irby, Matthew ; Davis, Ryan T. ; Kanner, Steven B. ; Gradia, Scott ; Donohoue, Paul D. ; Lilley, Graham W. J. ; Storlie, Meghan ; Banh, Lynda ; Edwards, Leslie

BACKGROUND AIMS:

Therapeutic disruption of immune checkpoints has significantly advanced the armamentarium of approaches for treating cancer. The prominent role of the programmed death-1 (PD-1)/programmed death ligand-1 axis for downregulating T cell function offers a tractable strategy for enhancing the disease-modifying impact of CAR-T cell therapy.

METHODS:

To address checkpoint interference, primary human T cells were genome edited with a next-generation CRISPR-based platform (Cas9 chRDNA) by knockout of the PDCD1 gene encoding the PD-1 receptor. Site-specific insertion of a chimeric antigen receptor specific for CD19 into the T cell receptor alpha constant locus was implemented to drive cytotoxic activity.

RESULTS:

These allogeneic CAR-T cells (CB-010) promoted longer survival of mice in a well-established orthotopic tumor xenograft model of a B cell malignancy compared with identically engineered CAR-T cells without a PDCD1 knockout. The persistence kinetics of CB-010 cells in hematologic tissues versus CAR-T cells without PDCD1 disruption were similar, suggesting the robust initial debulking of established tumor xenografts was due to enhanced functional fitness. By single-cell RNA-Seq analyses, CB-010 cells, when compared with identically engineered CAR-T cells without a PDCD1 knockout, exhibited fewer T_reg cells, lower exhaustion phenotypes and reduced dysfunction signatures and had higher activation, glycolytic and oxidative phosphorylation signatures. Further, an enhancement of mitochondrial metabolic fitness was observed, including increased respiratory capacity, a hallmark of less differentiated T cells.

CONCLUSIONS:

Genomic PD-1 checkpoint disruption in the context of allogeneic CAR-T cell therapy may provide a compelling option for treating B lymphoid malignancies.

2023-01-01·Frontiers in network physiology

Assessing cardiorespiratory interactions via lagged joint symbolic dynamics during spontaneous and controlled breathing.

Article

作者: Cairo, Beatrice ; De Maria, Beatrice ; Bari, Vlasta ; Gelpi, Francesca ; Porta, Alberto

Introduction: Joint symbolic analysis (JSA) can be utilized to describe interactions between time series while accounting for time scales and nonlinear features. JSA is based on the computation of the rate of occurrence of joint patterns built after symbolization. Lagged JSA (LJSA) is obtained from the more classical JSA by introducing a delay/lead between patterns built over the two series and combined to form the joint scheme, thus monitoring coordinated patterns at different lags. Methods: In the present study, we applied LJSA for the assessment of cardiorespiratory coupling (CRC) from heart period (HP) variability and respiratory activity (R) in 19 healthy subjects (age: 27-35 years; 8 males, 11 females) during spontaneous breathing (SB) and controlled breathing (CB). The R rate of CB was selected to be indistinguishable from that of SB, namely, 15 breaths·minute^-1 (CB15), or slower than SB, namely, 10 breaths·minute^-1 (CB10), but in both cases, very rapid interactions between heart rate and R were known to be present. The ability of the LJSA approach to follow variations of the coupling strength was tested over a unidirectionally or bidirectionally coupled stochastic process and using surrogate data to test the null hypothesis of uncoupling. Results: We found that: i) the analysis of surrogate data proved that HP and R were significantly coupled in any experimental condition, and coupling was not more likely to occur at a specific time lag; ii) CB10 reduced CRC strength at the fastest time scales while increasing that at intermediate time scales, thus leaving the overall CRC strength unvaried; iii) despite exhibiting similar R rates and respiratory sinus arrhythmia, SB and CB15 induced different cardiorespiratory interactions; iv) no dominant temporal scheme was observed with relevant contributions of HP patterns either leading or lagging R. Discussion: LJSA is a useful methodology to explore HP-R dynamic interactions while accounting for time shifts and scales.

2023-01-01·Environmental research

Cow bone-derived biochar enhances microbial biomass and alters bacterial community composition and diversity in a smelter contaminated soil

Article

作者: Li, Ronghua ; Shaheen, Sabry M ; Azeem, Muhammad ; Kareem, Hafiz A ; Zhang, Zenqqiang ; Li, Gang ; Riaz, Luqman ; Ali, Esmat F ; Ali, Amjad ; Arockiam Jeyasundar, Parimala Gnana Soundari ; Latif, Abdul ; Khan, Khalid S ; Majrashi, Ali ; Hussain, Qaiser ; Abbas, Fakhar ; Zhu, Yong-Guan

Bone waste could be utilized as a potential amendment for remediation of smelter-contaminated soils. Nevertheless, the influences of cow bone-derived biochar (CB) on soil microbial biomass and microbial community composition in multi-metal contaminated mining soils are still not clearly documented. Hence, the cow bone was used as feedstock material for biochar preparation and pyrolyzed at two temperatures such as 500 °C (CB500) and 800 °C (CB800), and added to a smelter soil at the dosage of 0 (unamended control), 2.5, 5, and 10% (w/w); then, the soil treatments were cultivated by maize. The CB effect on soil biochemical attributes and response of soil microbial biomass, bacterial communities, and diversity indices were examined after harvesting maize. Addition of CB enhanced total nutrient contents (i.e., total nitrogen up to 26% and total phosphorus P up to 27%) and the nutrients availability (i.e., NH₄ up to 50%; NO₃ up to 31%; Olsen P up to 48%; extractable K up to 18%; dissolved organic carbon up to 74%) in the treated soil, as compared to the control. The CB500 application revealed higher microbial biomass C (up to 66%), P (up to 41%), and bacterial gene abundance (up to 76%) than the control. However, comparatively a lower microbial biomass nitrogen and diversity indices were observed in the biochar (both with CB500 and CB800) treated soils than in the unamended soils. At the phylum level, the highest dose (10% of CB500 and CB800 resulted in contrasting effects on the Proteobacteria diversity. The CB500₁₀ favored the Pseudomonas abundance (up to 793%), Saccharibacteria (583%), Parcubacteria (138%), Actinobacteria (65%), and Firmicutes (48%) microbial communities, while CB800₁₀ favored the Saccharibacteria (386%), Proteobacteria (12%) and Acidobacteria (11%), as compared to the control. These results imply that CB500 and CB800 have a remarkable impact on microbial biomass and bacterial diversity in smelter contaminated soils. Particularly, CB500 was found to be suitable for enhancing microbial biomass, bacterial growth of specific phylum, and diversity, which can be useful for bioremediation of mining soils.

项与 CB-010 相关的新闻（医药）

2024-06-11

·研发客

细胞治疗遇冷，新型双抗热捧 | 2024 ASCO

// Summit股价上涨两倍以上，Affimed股价在6月3日这天上涨了69%。从ASCO前后的市场反馈和公司举动来看，双抗或许可以走出一波热度。回顾2024 ASCO其他文章，请点击赢了疗效输了股票 PFS超5年，肺癌竞争白热化 Trop-2 ADC靠联用续命？ 2024 ASCO（5月31日至6月4日）落下帷幕，数据发布与资本市场在这期间始终共振。有意思的是，尽管细胞疗法作为一种新兴的疗法给肿瘤治疗带来了突破，但相关公司的股价近来一直表现疲软，本次ASCO会议也不例外：开发同种异体（通用型）CAR-T疗法的Caribou Biosciences，由于发布的CB-010数据以及研发计划变化让投资者失望，在ASCO期间股价下跌了33%。而另一方面，两家开发双抗的肿瘤创新药公司由于数据优异股价飙升。Summit Therapeutics因为从康方生物引进的EGFR×PD-1双抗依沃西单抗头对头击败Keytruda而股价上涨两倍以上。专注于开发NK细胞接合器的生物技术公司Affimed则凭借在研药物AFM24与罗氏PD-L1抗体Tecentriq联合治疗的早期肺癌数据，股价在6月3日这天上涨了69%。不过，这些新疗法尚需要更多的临床数据来说服投资者。通用型细胞疗法的前景受到质疑尽管创始人是诺奖得主Jennifer Doudna，但自2021年在纳斯达克上市以来，Caribou的股价一路下滑，从最初的30多美元跌到如今的2美元不到。目前，该公司有三款产品正在开展用于血液癌症的1期研究。 Caribou以会议海报形式发布了其在研产品CB-010用于复发性和难治性B细胞非霍奇金淋巴瘤二线治疗的更新数据。该公司首席执行官 Rachel Haurwitz 认为，该结果支持 Caribou 的目标，即开发一种可以与目前批准的自体产品相媲美的抗 CD19 同种异体 CAR-T。但很显然，投资者并未被说服，该公司的股价在5月31日短暂上扬后几乎跌至历史最低水平。本次更新，Caribou在去年报告的16名剂量递增患者数据基础上，增加了剂量扩展部分的30名患者的数据。与之前的数据相比，ORR和CRR均有所下降，且整体来看6个月的无进展生存率（PFS）不佳。来源|ApexOnco 对此，Caribou的解释是，HLA的匹配情况才是影响疗效的决定性因素，而非药物剂量。Haurwitz 在 ASCO期间的一次采访中解释说，HLA匹配越好，CB-010 被患者免疫系统清除所需的时间就越长，因此产品的活性就越强。该公司已提交了一项回顾性分析来支持这一观点。分析显示，在 13 名 HLA 等位基因匹配为 4 个或更多的患者中，PFS 为 14.4 个月，而匹配为 3 个或更少的患者只有 2.8 个月。来源 | Caribou 为了证明这个理论，该公司计划另外招募20 名患者，接受至少有4个HLA等位基因匹配的产品治疗。这些患者的数据将于 2025 年上半年公布，Caribou 希望在开始关键试验之前获得这些结果，因此推迟了试验。尽管该公司表示，目前手头有 13 个不同批次的 CB-010 现货，可以为 90% 参加临床试验的患者提供至少有4个HLA等位基因匹配的产品，但计划更改意味着关键研究的开展还遥遥无期。最大赢家 Summit Therapeutics无疑是本次ASCO会议最大的赢家。5月30日该公司股价飙升了272%。不过这纯属意外之喜，因为股价上涨并非源于Summit在会议期间发布的数据，而是来自其合作伙伴、产品授权方康方生物发布的一项在中国开展的依沃西单抗与Keytruda对比，一线治疗非小细胞肺癌（NSCLC）的头对头研究的积极结果。虽然没有披露具体数据，但康方表示，依沃西单抗单药相比Keytruda单药治疗，在PD-L1阳性、局部晚期或转移性NSCLC患者中显著提高了PFS，且具有统计学意义和临床意义。另一家生物技术公司Affimed因报告了AFM24的早期阶段的肺癌数据而股价迅速上涨。AFM24 是一种基于 CD16A 的 NK 细胞接合器，靶向 EGFR 蛋白。根据会议海报，正在开展的AFM24-102研究初步结果显示，在 15 名接受铂类双药化疗和PD-(L)1抑制剂预治疗的转移性 EGFR 野生型 NSCLC 患者中，AFM24 和阿替利珠单抗联合治疗的疾病控制率为 73.3% (11/15)，包括 4 个OR（1 个CR和 3 个PR）。6月1日公司的新闻稿补充，13 名可评估的 EGFR 突变NSCLC 患者中有 4 名也达到了PR。来源 | ASCO海报新疗法尚需更多证明不过，这些带来股价飙升的新疗法尚需进一步的临床研究数据证实。 Summit在ASCO上发布的HARMONI-A研究展示了依沃西单抗联合化疗治疗接受EGFR TKI治疗后疾病进展的EGFR突变的NSCLC中国患者数据。研究的OS数据尚未达到，Summit在新闻稿中称，尽管基于该研究的结果，依沃西单抗已在中国成功获批，但是要获得美国FDA的批准，还需要更多的数据。为此，Summit自去年5月起已经开始招募美国患者参加HARMONI研究，此外，也在进行另一项针对一线NSCLC的HARMONI-3全球3期研究。而对于Affimed来说，AFM24并不是该公司当前的重点，其最主要的资产是AFM13（acimtamig）。与AFM24一样，AFM13也是基于该公司的ROCK（重定向优化细胞杀伤）平台开发的四价双特异性ICE（先天细胞接合器）。据Affimed的公开资料，ICE分子能够与先天免疫细胞（NK细胞或巨噬细胞）上的CD16A受体和肿瘤细胞上的特定受体结合，将先天免疫细胞和肿瘤细胞结合在一起。一旦这个结合建立，免疫细胞就会被激活，释放出直接杀死肿瘤细胞的因子。该公司认为，与其他抗体疗法相比，由 ROCK平台生成的 ICE分子通过高效、稳定地与 NK 细胞和巨噬细胞 CD16A 受体上的独特表位以高亲和力和亲和力结合，避免与人体自身循环的血清 IgG 竞争。来源|Affimed AFM13是Affimed开发的首个ICE分子，靶向CD30。该公司计划在今年上半年发布AFM13与Artiva的NK细胞产品AlloNK (AB101)联合治疗复发/难治性霍奇金淋巴瘤的LUMINICE-203 研究数据。因为现金短缺，今年1月该公司裁员50%以上，以期现有资金能维持其运营至2025年。对于AFM24，Affimed已经终止了AFM24-102研究胃癌队列和评估胰腺癌、胆道癌和肝细胞癌的篮子队列的招募，只为“尽快推进NSCLC项目”。而如果这些研究能获得积极结果，Affimed有希望获得投资者的青睐，摆脱资金危机。 2024 ASCO系列报道结束，明年ASCO再见！编辑 | 姚嘉 yao.jia@PharmaDJ.com 总第2134期访问研发客网站可浏览更多文章 www.PharmaDJ.com

ASCO会议细胞疗法临床结果抗体药物偶联物临床1期

2024-06-09

·药明康德

疾病控制率达100%的免疫联合疗法；使月度发作率下降98%的基因编辑疗法…… | 一周盘点

▎药明康德内容团队编辑本期看点 1. 新型口服双重抑制剂TU2218联用PD-1抑制剂pembrolizumab治疗晚期实体瘤患者，在一项1b期临床试验中的疾病控制率（DCR）达100%。 2. 用于治疗遗传性血管水肿（HAE）的在研体内CRISPR基因编辑疗法NTLA-2002早期临床数据亮眼，单次给药后使患者的月度发作率平均下降了98%。 3. 现货型基因疗法PRGN-2012治疗复发性呼吸乳头状瘤病（RRP）患者的1/2期临床试验达到主要终点，有望成为首个获得FDA批准的用于治疗RRP的疗法。 4. 男性无激素避孕药YCT-529完成了1a期临床试验，在临床前研究中，该候选疗法预防小鼠妊娠的有效率为99%，且100%可逆。药明康德内容团队整理 TU2218：公布1b期临床试验的中期数据 TiumBio公司公布了新型口服双重抑制剂TU2218联用PD-1抑制剂pembrolizumab治疗晚期实体瘤患者1b期临床试验的中期结果。TU2218靶向转化生长因子β受体1（TGFR1）和血管内皮生长因子受体2（VEGFR2）。肿瘤微环境中的TGF-ß和VEGF通路会干扰免疫检查点抑制剂的抗肿瘤活性，因此TU2218有望通过抑制这两种通路最大限度地提高免疫疗法的疗效。此次公布的结果显示，5名接受2期推荐剂量（RP2D）TU2218联用pembrolizumab治疗的患者的DCR为100%，其中两名患者达到了部分缓解（PR），3名患者达到了疾病稳定（SD）。所有剂量组中，12名接受联合治疗的患者中有2人达到了PR，6人达到了SD。在这项研究中，TU2218联用pembrolizumab的耐受性良好，没有观察到剂量限制性毒性（DLT），这与之前的单药治疗试验一致。 NTLA-2002：公布1期临床试验的长期数据 Intellia Therapeutics公司宣布其用于治疗遗传性血管水肿的在研疗法NTLA-2002的1期临床试验的长期数据。NTLA-2002是一种体内CRISPR基因编辑候选疗法，通过脂质纳米颗粒（LNP）以mRNA形式递送CRISPR-Cas9基因编辑系统，靶向敲除血浆前激肽释放酶（KLKB1）基因，以永久性降低血浆中激肽释放酶活性，从而防止遗传性血管水肿的发作。此次公布的结果显示，中位随访时间为20.1个月时，单次NTLA-2002治疗让患者的月均疾病发作率平均减少了98%，中度至重度发作平均减少了99%。在测试的每个剂量水平上，HAE发作率均显著减少。单次输注后，患者最长的无发作期超过26个月，并且仍在持续。此外，100%接受NTLA-2002治疗的患者在停止其他预防性治疗后无需再进行预防性治疗。 PRGN-2012：公布1/2期临床试验的新数据 Precigen公司公布了其现货型基因疗法PRGN-2012治疗复发性呼吸乳头状瘤病患者的1/2期临床试验数据。PRGN-2012旨在激发对抗受HPV6或HPV11感染细胞的免疫反应，以治疗RRP。此前，PRGN-2012已获得FDA和欧盟委员会授予的孤儿药资格，还获得了FDA授予的突破性疗法认定。此次公布的结果显示，该1/2期临床试验达到了主要的安全性和疗效终点。中位随访时间为20个月时，51%（18/35）接受PRGN-2012治疗的患者达到了完全缓解（CR），且不再需要进行手术治疗，CR持续时间超过12个月。86%的患者在接受PRGN-2012治疗后的一年内需要进行的手术次数较治疗前一年减少，从治疗前一年的中位次数4次减少到接受治疗后的0次。此外，PRGN-2012显著改善了达到CR患者的Derkay评分（一种用于测量RRP生长程度的量表）和生活质量评分。安全性方面，PRGN-2012的耐受性良好，无DLT，也没有＞2级的治疗相关不良事件。 ▲PRGN-2012的1/2期临床试验结果（图片来源：参考资料[9]）该公司计划在2024年下半年通过加速批准途径提交PRGN-2012的滚动生物制品许可申请（BLA）。新闻稿指出，如果获得批准，PRGN-2012有可能成为首个获得FDA批准用于治疗RRP的疗法。 YCT-529：公布1a期临床试验数据 YourChoice Therapeutics公司公布其男性无激素避孕药YCT-529的1a期临床试验结果。YCT-529是一种视黄酸受体-α（RAR-a）抑制剂，通过阻断RAR-α来阻止睾丸中精子的产生和释放。临床前研究表明，YCT-529在预防小鼠妊娠方面有99%的有效性，且100%可逆。该研究的结果表明，YCT-529是安全的。 C-CAR031：公布1期临床试验的初步数据阿斯利康（AstraZeneca）公布其GPC3靶向CAR-T疗法C-CAR031的最新临床试验结果。GPC3是一种在肝癌中过表达的表面抗原，该蛋白在健康组织中几乎不存在。C-CAR031是一种GPC3靶向的自体CAR-T疗法，这款CAR-T疗法还同时“装备”了TGFβ以抵抗免疫抑制微环境，以增强其效力。此次公布的结果显示，中位随访时间为5.82个月时，22例可评估疗效的GPC3阳性晚期肝细胞癌（HCC）患者的DCR为90.9%，客观缓解率为50.0%，且该疗法的安全性可控。阿斯利康的早期肿瘤学开发负责人Matt Hellmann博士在接受行业媒体STAT采访时表示：“这是首个在肝癌治疗上显示具疗效的CAR-T疗法。这也是GPC3靶点的首次临床验证。” ▲C-CAR031的疗效结果摘要（图片来源：参考资料[1]） CB-010：公布1期临床试验数据 Caribou Biosciences公司公布了其同种异体CAR-T细胞疗法CB-010治疗复发/难治性B细胞非霍奇金淋巴瘤患者的新数据。CB-010利用基因编辑技术生成，除了表达靶向CD19的嵌合抗原受体，还利用基因编辑技术敲除了免疫检查点蛋白PD-1的表达，旨在提高抗肿瘤活性的持久性。截至2024年4月1日的数据，CB-010的疗效和安全性可与已获批的自体CAR-T细胞疗法相媲美。13名部分人类白细胞抗原（HLA）匹配（≥4个等位基因）患者的总缓解率达92%，CR率为46%，中位无进展生存期（PFS）获得改善，为14.4个月。 ▲接受CB-010治疗患者的无进展生存曲线（图片来源：参考资料[4]） ▲接受CB-010治疗患者的疗效结果（图片来源：参考资料[4]） INB-200：公布1期临床试验的新数据 IN8bio公司公布其耐化疗的转基因自体γδ T细胞疗法INB-200用于治疗新确诊的多形性胶质母细胞瘤的积极早期数据。INB-200是一种强大的协同治疗方法，能在患者接受化疗时持续存在，并保持其识别、参与和杀死癌细胞的自然能力。截至2024年5月30日的数据，中位随访时间为11.7个月，92%接受INB-200治疗的可评估患者的中位PFS超过了7个月（即接受标准治疗方案的患者的中位PFS）。一名患有IDH突变神经胶质瘤的患者在接受治疗后的34.9+个月时仍然存活，且疾病没有进展。近期发表的一项IDH抑制剂治疗IDH突变脑胶质瘤患者的临床试验中，对照组患者的中位PFS为11.1个月，试验组患者的中位PFS为28.5个月。安全性方面，在任何队列中均未报告与治疗相关的严重不良事件、DLT、细胞因子释放综合征、输注反应或免疫效应细胞相关神经毒性综合征。 IFx-2.0：公布1b期临床试验数据 TuHURA Biosciences公司公布了其个体化的候选癌症疫苗IFx-2.0治疗对免疫检查点抑制剂（ICI）耐药的晚期Merkel细胞癌（MCC）和皮肤鳞状细胞癌（cSCC）患者的1b期试验的初步结果。该候选疗法旨在克服患者对ICI的原发性耐药。此次公布的结果显示，连续三周每周给药一次IFx-2.0的耐受性良好。5名此前接受ICI治疗后在3.8个月内疾病就发生进展的晚期MCC患者中，有4人在接受IFx-2.0治疗后重新对ICI治疗产生了持久的应答，包括1例CR、1例病理完全缓解（pCR）和两例PR。患者的平均缓解时间为25个月，其中两名患者已分别持续缓解19个月和23个月，并且仍在持续缓解中。 MDNA11：公布1/2期临床试验的新数据 Medicenna Therapeutics公司公布了其下一代长效IL-2超级激动剂MDNA11治疗晚期实体瘤的新临床结果。MDNA11具有优秀的CD122（IL-2受体β）结合作用，而没有CD25（IL-2受体α）亲和力，从而能优先刺激癌症杀伤效应T细胞和NK细胞。此次公布的结果显示，MDNA11的耐受性良好，没有报告DLT和血管渗漏综合征。MDNA11在胰腺癌患者中表现出持久的缓解，1例转移性胰腺导管腺癌患者在基线时存在的所有病灶均完全消退，已维持超过104周，在停止治疗4个月后仍然保持着缓解。一例双检查点抑制剂治疗后进展的黑色素瘤患者的靶病灶在第28周时完全消退，在第44周的扫描时靶病灶仍保持完全消退。目前，该患者仍在接受MDNA11的治疗，非靶病灶也在继续消退。 WTX-124：公布1/1b期临床试验数据 Werewolf Therapeutics公司公布了其条件激活的白介素-2（IL-2）候选疗法WTX-124治疗接受过ICI治疗的局部晚期或转移性实体瘤患者的1/1b期临床试验数据。结果显示，WTX-124在此类患者中具有临床活性，且耐受性良好。截至2024年5月1日的数据，接受WTX-124单药治疗的患者中有1人获得了持久并经过确认的CR，2人达到了PR。获得缓解的患者在治疗的前两个治疗周期内就出现了缓解，并且靶病灶实现了100%的消退。此外，没有发现WTX-124联用pembrolizumab出现新的安全信号。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看） [1] Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC). 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Retrieved June 7, 2024, from https://www.businesswire.com/news/home/20240603691086/en [25] Cyclacel Pharmaceuticals Reports New Clinical Data at 2024 ASCO Annual Meeting Highlighting Oral Fadraciclib’s Potential as a Precision Medicine for Cancer. Retrieved June 7, 2024, from https://investor.cyclacel.com/news-releases/news-release-details/cyclacel-pharmaceuticals-reports-new-clinical-data-2024-asco [26] Obsidian Therapeutics Announces Additional OBX-115 Safety and Efficacy Data in Oral Presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. Retrieved June 7, 2024, from https://www.businesswire.com/news/home/20240603008329/en [27] Replimune Presents RP1 Data from the IGNYTE anti-PD1 Failed Melanoma Cohort and RP2 Data in Uveal Melanoma at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. Retrieved June 7, 2024, from https://ir.replimune.com/news-releases/news-release-details/replimune-presents-rp1-data-ignyte-anti-pd1-failed-melanoma [28] RS Oncology Announces Positive Data from a Phase 1 Clinical Trial of RSO-021, a First-in-Class Therapeutic for Malignant Pleural Mesothelioma. Retrieved June 7, 2024, from https://www.businesswire.com/news/home/20240603559175/en [29] Ascendis Pharma Presents New Data and Updated Results from Phase 1/2 IL-Believe Trial at ASCO 2024. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/03/2892565/0/en/Ascendis-Pharma-Presents-New-Data-and-Updated-Results-from-Phase-1-2-IL-Believe-Trial-at-ASCO-2024.html [30] Scholar Rock Presents New Data from SRK-181 Phase 1 DRAGON Trial at ASCO 2024 Annual Meeting. Retrieved June 7, 2024, from https://www.businesswire.com/news/home/20240603004778/en [31] invoX Pharma Presents Positive Clinical Data from Phase 1 Study of FS222 in Patients with Advanced Solid Tumours at the 2024 American Society of Clinical Oncology Annual Meeting. Retrieved June 7, 2024, from https://www.businesswire.com/news/home/20240603068133/en [32] Eledon Presents Updated Data from Ongoing Phase 1b Trial Evaluating Tegoprubart for Prevention of Rejection in Kidney Transplantation. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/03/2892558/0/en/Eledon-Presents-Updated-Data-from-Ongoing-Phase-1b-Trial-Evaluating-Tegoprubart-for-Prevention-of-Rejection-in-Kidney-Transplantation.html [33] ImmuneOncia Announces Biomarker Results from Phase 1 Clinical Trial of CD47 Antibody at ASCO. Retrieved June 7, 2024, from https://www.businesswire.com/news/home/20240603017832/en [34] Entera Bio Reports Phase 1 Clinical Data of First-in-Class, Oral PTH(1-34) Peptide Candidate (EB612) for Patients with Hypoparathyroidism at ENDO 2024. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/03/2892199/0/en/Entera-Bio-Reports-Phase-1-Clinical-Data-of-First-in-Class-Oral-PTH-1-34-Peptide-Candidate-EB612-for-Patients-with-Hypoparathyroidism-at-ENDO-2024.html [35] Enlivex Receives Regulatory Authorization for the Initiation of a Placebo-Controlled Phase I/II Trial Evaluating Allocetra in Up To 46 Patients with Thumb Osteoarthritis. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/03/2892206/0/en/Enlivex-Receives-Regulatory-Authorization-for-the-Initiation-of-a-Placebo-Controlled-Phase-I-II-Trial-Evaluating-Allocetra-in-Up-To-46-Patients-with-Thumb-Osteoarthritis.html [36] Indaptus Therapeutics Announces New Positive Data from Ongoing Phase 1 Trial of Decoy20. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/03/2892212/0/en/Indaptus-Therapeutics-Announces-New-Positive-Data-from-Ongoing-Phase-1-Trial-of-Decoy20.html [37] Alkermes Presents Data From Phase 1b Study of ALKS 2680 Demonstrating Improved Wakefulness in Patients With Narcolepsy Type 1 at SLEEP 2024. Retrieved June 7, 2024, from https://www.prnewswire.com/news-releases/alkermes-presents-data-from-phase-1b-study-of-alks-2680-demonstrating-improved-wakefulness-in-patients-with-narcolepsy-type-1-at-sleep-2024-302161336.html [38] IDRx Reports Updated Preliminary Phase 1 Data from Ongoing Phase 1/1b StrateGIST 1 Trial Supporting Best-in-Class Potential for IDRX-42 in Patients with GIST. Retrieved June 7, 2024, from https://www.businesswire.com/news/home/20240531639390/en [39] Century Therapeutics Presents Interim Results from Phase 1 ELiPSE-1 Study at ASCO 2024 Annual Meeting. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/03/2892097/0/en/Century-Therapeutics-Presents-Interim-Results-from-Phase-1-ELiPSE-1-Study-at-ASCO-2024-Annual-Meeting.html [40] MediciNova Announces Data from Phase 1b/2a Clinical Trial of MN-166 (ibudilast) in Glioblastoma Patients at the American Society of Clinical Oncology (ASCO) Annual Meeting 2024. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/03/2892064/7767/en/MediciNova-Announces-Data-from-Phase-1b-2a-Clinical-Trial-of-MN-166-ibudilast-in-Glioblastoma-Patients-at-the-American-Society-of-Clinical-Oncology-ASCO-Annual-Meeting-2024.html [41] FibroGen Announces FDA Clearance of Investigational New Drug Application for FG-3165, a Galectin-9 Targeting Monoclonal Antibody, for the Treatment of Patients with Solid Tumors. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/03/2892568/0/en/FibroGen-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-FG-3165-a-Galectin-9-Targeting-Monoclonal-Antibody-for-the-Treatment-of-Patients-with-Solid-Tumors.html [42] STORM Therapeutics Presented Interim Phase 1 Clinical Data on its METTL3 RNA Methyltransferase Inhibitor STC-15 at ASCO 2024. Retrieved June 7, 2024, from https://www.prnewswire.com/news-releases/storm-therapeutics-presented-interim-phase-1-clinical-data-on-its-mettl3-rna-methyltransferase-inhibitor-stc-15-at-asco-2024-302160864.html [43] Black Diamond Therapeutics Presents Promising BDTX-1535 Clinical Data in Patients with Recurrent Glioblastoma at 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. Retrieved June 7, 2024, from https://investors.blackdiamondtherapeutics.com/news-releases/news-release-details/black-diamond-therapeutics-presents-promising-bdtx-1535-clinical [44] Immunocore reports updated Phase 1 data of brenetafusp (IMC-F106C), an ImmTAC bispecific targeting PRAME, in immune checkpoint pre-treated cutaneous melanoma patients at ASCO 2024. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/05/31/2891735/0/en/Immunocore-reports-updated-Phase-1-data-of-brenetafusp-IMC-F106C-an-ImmTAC-bispecific-targeting-PRAME-in-immune-checkpoint-pre-treated-cutaneous-melanoma-patients-at-ASCO-2024.html [45] Kymera Therapeutics Presents New Clinical Data from Ongoing Phase 1 Trial of MDM2 Degrader KT-253 at ASCO Annual Meeting. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/01/2891812/0/en/Kymera-Therapeutics-Presents-New-Clinical-Data-from-Ongoing-Phase-1-Trial-of-MDM2-Degrader-KT-253-at-ASCO-Annual-Meeting.html [46] Accutar Biotechnology Presents Phase 1 Data of AC699 Monotherapy in Patients with ER+ / HER2- Breast Cancer at ASCO 2024. Retrieved June 7, 2024, from https://www.businesswire.com/news/home/20240601126229/en [47] Molecular Partners Presents Positive Data From Completed Phase 1 Trial Of MP0317 (FAP X CD40 DARPin) Monotherapy In Patients With Advanced Solid Tumors At ASCO 2024. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/01/2891809/0/en/Molecular-Partners-Presents-Positive-Data-From-Completed-Phase-1-Trial-Of-MP0317-FAP-X-CD40-DARPin-Monotherapy-In-Patients-With-Advanced-Solid-Tumors-At-ASCO-2024.html [48] Updated Data from the Phase 1/2 Study of Olomorasib in KRAS G12C-Mutant Advanced Solid Tumors Presented at the 2024 ASCO® Annual Meeting. Retrieved June 7, 2024, from https://www.prnewswire.com/news-releases/updated-data-from-the-phase-12-study-of-olomorasib-in-kras-g12c-mutant-advanced-solid-tumors-presented-at-the-2024-asco-annual-meeting-302160829.html [49] ALX Oncology Presents First Evorpacept Combination Data with an Antibody-Drug Conjugate from Phase 1 ASPEN-07 Clinical Trial in Patients with Advanced Bladder Cancer. Retrieved June 7, 2024, from https://www.globenewswire.com/news-release/2024/06/02/2891851/0/en/ALX-Oncology-Presents-First-Evorpacept-Combination-Data-with-an-Antibody-Drug-Conjugate-from-Phase-1-ASPEN-07-Clinical-Trial-in-Patients-with-Advanced-Bladder-Cancer.html 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床结果基因疗法免疫疗法临床2期

2024-05-29

·FierceBiotech

Biotech faces a reckoning: ‘We've lost our luster in cell therapies’

The biopharma industry is facing a reckoning; Will the market ever fully accept cell therapy? This story is the first part in a four-part series about cell therapy, created by the Fierce Biotech team. Gabrielle Masson, Helen Floersh, James Waldron and Max Bayer contributed reporting to this series. Cell therapy has been slashed by a thousand cuts over the past few years, from the failure of autologous CAR-T to live up to expectations, to market challenges to manufacturing woes. And now, the focus has shifted to autoimmune conditions. The biopharma industry is now facing a reckoning; Will the market ever fully accept these treatments? “We've lost our luster in cell therapies,” said Eric Schmidt Ph.D., biotech analyst for Cantor Fitzgerald, in an interview. “It's honestly been a pretty depressing last 12 months or so.” Sami Corwin, Ph.D., a research analyst at William Blair, calls this moment in time for cell therapy “a pivot.” Big Pharmas like Sanofi and Bristol Myers Squibb have begun pulling back from the cell therapy space, confronted with manufacturing challenges and the reality of marketing a personalized therapy. BMS shut down a California research center that was focused on the tumor microenvironment in April as part of a major restructuring. “The changes in our Cell Therapy Organization will streamline and focus efforts on the most promising areas, enabling us to maximize our inline assets, while building the foundation necessary to deliver on our best-in-class pipeline,” a spokesperson for BMS said at the time. Days later, BMS signed a $65 million upfront deal with Repertoire to work on tolerizing vaccines for autoimmune diseases, underscoring the pharma's interest in autoimmune but not cell therapy. Also undergoing a pipeline reorganization, Sanofi shuttered legacy business Kiadis, which had been working on developing next-gen, ‘off-the-shelf,’ natural killer cell therapies. All of this has led to a muddled present, in which biotechs are walking away from oncology with uncertain partnership opportunities for the near future. “I guess in part, you can blame capacity and in part you can probably blame the complexity of the therapy. Or maybe you blame the competition as well,” Schmidt said. Even as cell therapies have put out strong data in oncology, the modality has been overshadowed by bispecifics, which have grown quickly in cancer care and surpassed sales for approved cell therapies in the myeloma space, specifically. “From a commercial standpoint, the autologous products … just haven't really knocked the cover off the ball the way that people might have been hopeful, given how strong the clinical data were,” Schmidt said, speaking specifically to CD19 cell therapies, which include Gilead’s Tecartus, Yescarta and Kymriah and Bristol Myers Squibb’s Breyanzi. Gilead has achieved the greatest success with Yescarta, which generated $380 million in net sales for the first quarter. Schmidt calls this the one “shining, positive example” in the field of approved therapies. The remaining approved cell therapies are all at or below $157 million. https://public.flourish.studio/visualisation/17948038/ But these products have not lived up to the hype elsewhere. “And that’s a real problem,” Schmidt said. “I don't know why. And I’m kind of hard-pressed to think it's just about supply and complexity and delivery.” Companies have also made slow progress in moving cell therapies into solid tumors, although some progress has been made including the approval of Iovance Biotherapeutics' Amtagvi in melanoma. Mustang Bio and City of Hope also recently showed in an early-stage trial that CAR-T therapy may have a future in the difficult brain cancer glioblastoma. For Allogene’s Zachary Roberts, M.D., Ph.D., the problems that have dogged cell therapy are simply because the tech wasn’t quite ready when all of these treatments rushed into the clinic. “I'm fond of saying that autologous products probably would not have been the first cell therapies approved, had we had the advanced gene editing tools that we have today,” said Roberts, EVP of R&D and chief medical officer. “So autologous products, as transformational as they have been, I believe, are essentially a stepping stone to the more cutting-edge allogeneic products like ours, and I'm excited by the in vivo CAR field, although they're still years away, and watching those data develop.” Cindy Perettie, global head of Gilead’s Kite Pharma unit, said that preclinical data does not translate as well into humans, so there is a huge amount of risk moving things into the clinic. “Having that phase one bake-off or horse race is really critical in these,” she said. Nevertheless, biotechs remain committed to cell therapy. Companies in the space are now going to have to find a way to justify the continued push and bring investors back around. “We have no idea as an investment community where the bar will be drawn,” Schmidt said. “As you go forward over the next 12 months, there will be a ton of cards to turn over, a ton of learnings.” https://omny.fm/shows/the-top-line/fulfilling-the-promise-of-cell-gene-therapies-thro Finding the spotlight The definition of cell therapy is vast and each specific technology has its challenges. Gene-edited cell therapies, for instance, are about to get a huge market test with the recent approval of sickle cell treatments Casgevy (Vertex Pharma and CRISPR Therapeutics) and Lyfgenia (bluebird bio). Both had huge price tags slapped on them and will need to confront the realities of a payer environment that might not be ready for them. That’s another story, however. Other types of cell therapy include CAR natural killer (NK) cells or T cell receptor (TCR) modified T cells. According to Schmidt, the biotechs working on NK cells have all “pretty much given up,” turning as well to autoimmune and “hoping that the bar is lower.” “Everyone who's got a platform has repositioned itself to autoimmune disease, more on hope than on any data,” he said. It’s CAR-T cell therapy that has made the greatest splash in the clinic, only to be sucked back out to sea with reports of relapse among patients. One of the first major corrections in CAR-T, which is sometimes referred to as cell-based gene therapy, was when autologous candidates were swapped out for so-called “off the shelf” allogeneic therapies that used donated cells rather than a patient’s own. This was said to ease the manufacturing and patient burden and speed turnaround time. Many first-gen allogenic biotechs emerged around 2018 with great promise, only to stutter, according to Corwin and Schmidt. “Outside the autologous products there’s been nothing to cheer about from a clinical standpoint,” Schmidt said. “The allogeneic therapies have, for the most part, taken a step backward.” Allogene stopped two trials of a CAR-T candidate in advanced lymphoma to focus on minimal residual disease in January. The move will slide cemacabtagene ansegedleucel (cema-cel) to the seventh line of treatment, where a potential market could exist as doctors tend to monitor sixth-line patients for the 30% who relapse. Caribou Biosciences, after being dogged by relapses among patients, repositioned itself with a partially matched allogeneic product—not the same as an off-the-shelf option, according to Schmidt. He said the company, which was co-founded by Nobel laureate Jennifer Doudna, Ph.D., is “on thin ice.” While the bulk of Caribou's pipeline remains focused on cancer, the company was just approved to test CB-010 in autoimmune, too. The trial will cover two types of lupus, lupus nephritis and extra renal lupus. "We're very encouraged by the initial safety and efficacy data that we've seen with CB-010 in oncology and that really motivated us to choose to also invest in developing it in parallel in lupus," Caribou CEO Rachel Haurwitz told investors at the BofA Securities 2024 Healthcare Conference earlier this month. The chief executive remains confident in the oncology side of CB-010's development program as well, with the company poised to unveil data at the upcoming American Society of Clinical Oncology meeting this week. Not ready to give up on its CAR NK technology, Nkarta was cleared by the FDA last fall to test a candidate called NKX019 in lupus, a move that investors cheered. The allogeneic, CD19-directed CAR NK cell therapy was already in clinical testing for B-cell malignancies. Data from the oncology trial revealed in March showed sharply falling response rates, compared to an earlier cohort. Even CRISPR Tx, which is one of few companies to have a cell therapy approved with the Vertex-partnered Casgevy, pivoted its pipeline in December 2023 toward autoimmune. Some companies are continuing to try and prove autologous therapies can thrive, bolstered by the regulatory approvals that have come. BioNTech has been working on its manufacturing process to prepare the CAR-T BNT211 for pivotal trials. The German biotech signed a $250 million upfront deal with Autolus Therapeutics in February to use the company’s manufacturing technology. In return, BioNTech is supporting Autolus’ autologous CD19 CAR-T called obe-cel, which is currently awaiting an FDA decision for B-cell acute lymphoblastic leukemia. “I am a huge believer in cell therapy. And I think that we are still very much in the first chapter ... And I think what we're doing right now as a field is looking for ways to accelerate and simplify what we have to do with cell therapy to bring approvals in quicker and in interesting ways,” Allogene’s Roberts said. But now, thanks to some key studies out of Germany, the science on cell therapy has improved and the ability to address larger markets could be within reach. Corwin believes companies that are onto next-gen allogenic may “come back into the spotlight now.” Editor's Note: This story is part of a series on cell therapy. The second part will be published on May 30. This story was updated on May 29 at 3:23 p.m. ET, to include comments from Caribou CEO Rachel Haurwitz.

细胞疗法免疫疗法ASCO会议临床研究基因疗法

100 项与 CB-010 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
难治性B细胞淋巴瘤	临床1期	美国	Caribou Biosciences, Inc.	2021-05-26
难治性B细胞淋巴瘤	临床1期	澳大利亚	Caribou Biosciences, Inc.	2021-05-26
难治性B细胞淋巴瘤	临床1期	以色列	Caribou Biosciences, Inc.	2021-05-26
复发性非霍奇金淋巴瘤	临床1期	美国	Caribou Biosciences, Inc.	2021-05-26
复发性非霍奇金淋巴瘤	临床1期	澳大利亚	Caribou Biosciences, Inc.	2021-05-26
复发性非霍奇金淋巴瘤	临床1期	以色列	Caribou Biosciences, Inc.	2021-05-26
狼疮性肾炎	临床申请批准	美国	Caribou Biosciences, Inc.	2024-04-06

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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


NCT04637763 (ANTLER, ASCO2024)	临床1期	B细胞淋巴瘤 CD19 \| PD-1	16	CB-010 at 40 x 106 CAR-T cells	餘衊築襯簾獵繭鹹淵簾(窪憲構窪簾膚憲壓築網) = 夢網壓範夢遞獵襯蓋襯願製範範網顧膚窪衊積 (艱糧遞夢鏇廠鹹築繭餘 ) 更多	积极	2024-05-24
				CB-010 at 80 x 106 CAR-T cells	餘衊築襯簾獵繭鹹淵簾(窪憲構窪簾膚憲壓築網) = 衊願窪齋鑰顧廠壓願鏇願製範範網顧膚窪衊積 (艱糧遞夢鏇廠鹹築繭餘 ) 更多
NCT04637763 (ANTLER, EHA2024) 人工标引	临床1期	非霍奇金淋巴瘤	16	CB-010	醖衊襯齋顧艱築築網鬱(糧憲範衊製糧鏇窪淵選) = 衊糧觸觸憲積網築觸鬱簾鹽遞範網網憲觸鬱選 (鹽遞簾願鬱製糧淵襯顧 ) 更多	积极	2024-05-14
				CB-010 (LBCL)	醖衊襯齋顧艱築築網鬱(糧憲範衊製糧鏇窪淵選) = 製窪廠獵廠齋膚廠艱鏇簾鹽遞範網網憲觸鬱選 (鹽遞簾願鬱製糧淵襯顧 ) 更多
NCT04637763 (ANTLER, EHA2024)	临床1期	B细胞淋巴瘤	16	CB-010 at 40 x 106 CAR-T cells	齋構鏇窪獵繭築壓衊範(艱齋鏇範襯憲襯艱遞鏇) = 8/16; 50% 觸選觸簾範積顧壓壓廠 (窪範構艱獵範願選觸壓 ) 更多	积极	2024-05-14
				CB-010 at 80 x 106 CAR-T cells
NCT04637763 (ANTLER, Corporate Publications) 人工标引	临床1期	难治性B细胞淋巴瘤	6	CB-010	網鹹淵選窪鹹淵淵醖齋(夢鑰齋鹹製築顧餘襯積) = 40x10^6 CAR-T cells（grade 1 CRS 33% and grade 3 ICANS 17%）蓋製鑰齋鏇築憲構鏇淵 (獵夢餘願繭簾蓋顧構壓 )	积极	2022-06-10