Hepatic Artery Transfusion of NKG2D CAR-T Cells to Treat Patients with Previously Treated Liver Metastatic Colorectal Cancer: a Prospective, Multicenter Clinical Trial

开始日期2021-09-01

申办/合作机构

广州医科大学附属第三医院

ChiCTR2000038015 / Recruiting早期临床1期IIT

One-Center, Open-Label, Single-Arm Clinical Study of the Safety and Effectiveness of NKG2D CAR-T Cells Infusion in the Treatment of Relapsed or Refractory NKG2DL+ Tumors

开始日期2020-09-10

申办/合作机构-

NCT03612739 / Withdrawn临床1期

An Open-label, Phase I Study to Assess the Safety of NKR-2 Treatment Administered Concurrently With 5-azacytidine in Treatment-naïve Acute Myeloid Leukemia or Myelodysplastic Syndrome Patients Not Candidates for Intensive Therapy

This open-label Phase I study aims to define the recommended dose for further clinical development the NKR-2 treatment administered concurrently with AZA in treatment-naïve AML/MDS patients not candidates for intensive chemotherapy or hematopoietic stem cell transplantation.
This Phase I study is divided into three sequential cohorts evaluating three different dose-levels of NKR-2 (1x108, 3x108 and 1x109 NKR-2 per injection) using a 3+3 design evaluate. Further patients will be enrolled at the RecD to reach 9 evaluable patients in total at the RecD.
The study consists of a screening phase, a treatment administration phase and a follow-up phase divided into treatment follow-up (TFU) and long-term safety follow-up (LTSFU). For each patient who received at least one NKR-2 administration, the overall study duration will be 15 years after first NKR-2 administration.

开始日期2018-12-01

申办/合作机构

Celyad Oncology SA

100 项与 CYAD-01(Dartmouth College) 相关的临床结果

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100 项与 CYAD-01(Dartmouth College) 相关的转化医学

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100 项与 CYAD-01(Dartmouth College) 相关的专利（医药）

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项与 CYAD-01(Dartmouth College) 相关的文献（医药）

2024-11-01·INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

Thermosensitive hyaluronic acid-manganese-capsaicin complex nanogel improving NKG2D/CAR-T melanoma treatment through adjusting tumor microenvironment

Article

作者: Xu, Hui ; Dai, Hongjiu ; Wu, Hangyi ; Lv, Huixia ; Wang, Weiqin ; Ma, Xiaxia ; Gu, Wanyue ; Zhang, Zhenhai

Intratumorally injection of CAR-T cells to treat melanoma can reduce the incidence of systemic side effects and ensure an adequate concentration of CAR-T cells. However, few targeting ligands and hostile tumor microenvironment (TME) inhibit the CAR-T cells' survival and infiltration. An in situ hyaluronic acid‑manganese-capsaicin complex nanogel (HA-Mn-CAP Gel) was designed by forming complex nanogel based on the main skeleton material of hyaluronic acid (HA). It targeted CD44 and TRPV₁ receptors through HA and CAP, concentrated and released Mn at melanoma, subsequently relieving the hypoxia in the tumor and increasing the expression of CAR-T cells' specific ligands. Cell experiments showed that HA-Mn-CAP Gel significantly enhanced the expression of representative NKG₂D ligands (MICA/B and ULBP_2/5/6) >2.7 times on A375 melanoma cells. Sequential administration of HA-Mn-CAP Gel and NKG₂D/CAR-T increased the tumor inhibition rate about 1.5 times that of the NKG₂D/CAR-T group in melanoma-bearing NSG mice. The results of immunohistochemistry and immunofluorescence assays showed that the combined HA-Mn-CAP Gel and NKG₂D/CAR-T significantly increased the proliferation and infiltration of T cells, especially for CD8⁺ cells. Therefore, the new promising strategy of increasing the target ligand expression and adjusting TME before administering CAR-T cells is suitable for treating solid tumors.

2024-10-01·MOLECULAR THERAPY

Intrinsic ADRB2 inhibition improves CAR-T cell therapy efficacy against prostate cancer

Article

作者: Ajmal, Iqra ; Jiang, Wenzheng ; Yao, Jie ; Farooq, Muhammad Asad ; Duan, Yixin ; Hui, Xinhui ; Gao, Yaoxin ; Chen, Yiran ; Du, Bingtan ; Ge, Yujia ; Ren, Yaojun

Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in patients with solid tumors. Recent in vitro and in vivo data have shown that adrenoceptor beta-2 (ADRB2) is a novel checkpoint receptor that inhibits T cell-mediated anti-tumor responses. To inhibit ADRB2-mediated inhibitory signaling, we downregulated ADRB2 in CAR-T (shβ₂-CAR-T) cells via RNA interference, assessed different parameters, and compared them with conventional second-generation CAR-T cells. ADRB2 knockdown CAR-T cells exhibited enhanced cytotoxicity against prostate cancer cell lines in vitro, by increasing CD69, CD107a, GzmB, IFN-γ, T-bet, and GLUT-1. In addition, ADRB2 deficiency led to improved proliferation, increased CD8/CD4 T cell ratio, and decreased apoptosis in CAR-T cells. shβ₂-CAR-T cells expressed more Bcl-2 and led to the generation of more significant proportions of T central memory cells. Finally, the ZAP-70/NF-κB signaling axis was shown to be responsible for the improved functions of novel CAR-T cells. In tumor-bearing mice, shβ₂-CAR-T cells performed better than conventional CAR-T cells in eradicating prostate tumors. The study provides the basis for future clinical and translational CAR-T cell research to focus on adrenergic stress-mediated challenges in the tumor microenvironment of stressed tumors.

2024-09-01·HemaSphere

Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A‐rearranged acute leukemia

Article

作者: Castor, Anders ; Falqués‐Costa, Ton ; Fioretos, Thoas ; Rissler, Vendela ; Lausen, Birgitte ; Zhang, Qirui ; Hagström‐Andersson, Anna K. ; Marquart, Hanne V. H. ; Sturesson, Helena ; Hyrenius‐Wittsten, Axel ; Ovlund, Tina ; Pilheden, Mattias

Abstract:

Activating FLT3 and RAS mutations commonly occur in leukemia with KMT2A‐gene rearrangements (KMT2A‐r). However, how these mutations cooperate with the KMT2A‐r to remodel the epigenetic landscape is unknown. Using a retroviral acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3, we show that FLT3ITD, FLT3N676K, and NRASG12D remodeled the chromatin accessibility landscape and associated transcriptional networks. Although the activating mutations shared a common core of chromatin changes, each mutation exhibits unique profiles with most opened peaks associating with enhancers in intronic or intergenic regions. Specifically, FLT3N676K and NRASG12D rewired similar chromatin and transcriptional networks, distinct from those mediated by FLT3ITD. Motif analysis uncovered a role for the AP‐1 family of transcription factors in KMT2A::MLLT3 leukemia with FLT3N676K and NRASG12D, whereas Runx1 and Stat5a/Stat5b were active in the presence of FLT3ITD. Furthermore, transcriptional programs linked to immune cell regulation were activated in KMT2A‐r AML expressing NRASG12D or FLT3N676K, and the expression of NKG2D‐ligands on KMT2A‐r cells rendered them sensitive to CAR T cell‐mediated killing. Human KMT2A‐r AML cells could be pharmacologically sensitized to NKG2D‐CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D‐ligand levels. Co‐treatment with LBH589 and NKG2D‐CAR T cells enabled robust AML cell killing, and the strongest effect was observed for cells expressing NRASG12D. Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation‐specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.

项与 CYAD-01(Dartmouth College) 相关的新闻（医药）

2023-02-12

·药明康德

客观缓解率达100%的CAR-T疗法、显著降低脑卒中患者死亡率的神经保护剂… | 一周盘点

▎药明康德内容团队编辑本期看点1. 医院制造的CAR-T细胞疗法GLPG5201用于治疗慢性淋巴细胞白血病和小淋巴细胞淋巴瘤，早期临床结果亮眼，客观缓解率达100%，完全缓解率达86%。2. 靶向BCMA的自体CAR-T细胞疗法NXC-201用于治疗多发性骨髓瘤，2期推荐剂量下的总缓解率达90%。3. 以高特异性作用于TLR4的神经保护剂ApTOLL联合血管内治疗，显著降低缺血性脑卒中患者的死亡率。4. 靶向NKG2D配体的候选CAR-T细胞疗法的概念验证试验结果积极，支持此类疗法的进一步开发。药明康德内容团队整理GLPG5201：公布1/2期临床试验数据Galapagos公司公布了其可在护理点制造的CAR-T细胞疗法GLPG5201的1/2期临床试验结果。靶向CD19的CAR-T治疗具潜力提高患有多种B细胞恶性肿瘤患者的生存率，例如慢性淋巴细胞白血病（CLL）和小淋巴细胞淋巴瘤（SLL）。该公司正在评估医院制造的GLPG5201在复发/难治性（RR）CLL和SLL患者中的可行性、安全性和有效性，这些患者伴或不伴Richter转化（RT）。研究结果显示，医院制造的GLPG5201是可行的，该在研CAR-T细胞疗法能在体内持续且良好地扩增。截至2023年1月9日，7例被诊断为RR-CLL的患者（4例伴RT）的客观缓解率（ORR）达到100%，其中86%（6/7）的患者达到完全缓解（CR），所有伴RT的患者均获得了CR。报告的持续缓解时间已达7.9个月，后续的随访还在进行中。仅有1例患者在达到PR后复发，复发的肿瘤为CD19阴性，且该患者被确诊为RT。安全性方面，GLPG5201表现出可接受的安全性，未观察到免疫效应细胞相关神经毒性综合征（ICANS），观察到的细胞因子释放综合征（CRS）不超过2级。NXC-201：公布1期临床试验的新数据Nexcella公司公布了其靶向BCMA的自体CAR-T细胞疗法NXC-201的1期试验最新数据。该研究旨在评估NXC-201用于治疗复发/难治性多发性骨髓瘤（RRMM）的安全性和有效性。截至2022年10月23日的数据，NXC-201在RRMM患者中表现出潜在有意义的疗效和持久的反应。中位随访时间为146天时，在包含所有剂量组中42位可评估的RRMM患者的总缓解率（ORR）为83%，完全缓解（CR）率或严格意义的完全缓解（sCR）率为50%。在接受2期临床推荐剂量（RP2D）NXC-201的MM患者中，根据国际骨髓瘤工作组的标准，ORR达90%，59%（17/29）的患者达到CR或sCR。此外，NXC-201的耐受性良好，42例可评估的患者中未观察到ICANS，所见CRS为可控。此次公布的数据支持NXC-201作为潜在可在门诊使用的CAR-T细胞疗法。ApTOLL：公布1b/2a期临床试验数据aptaTargets公司公布了其Toll样受体4（TLR4）拮抗剂ApTOLL联合血管内治疗（EVT）用于治疗急性缺血性卒中患者的早期临床结果。卒中可能由流向大脑的血流量显著减少或脑血管破裂出血引起，其中最常见的类型为缺血性卒中（约占85%）。ApTOLL是一种潜在“first-in-class”的神经保护剂，能够以高特异性作用于TLR4，阻断缺血性卒中后发生的炎症反应。此次公布的是一项多中心、双盲、随机、安慰剂为对照的试验，共纳入151例患者。患者被随机分配接受两种剂量的ApTOLL或安慰剂。所有患者都接受了机械血栓切除术，伴或不伴溶栓剂。研究结果显示，与安慰剂组相比，高剂量ApTOLL组的死亡率从18%降低至5%，高剂量ApTOLL组在最终梗死体积的减少和美国国立卫生研究院72小时卒中量表（NIHSS）评分方面的改善均具有统计学意义。研究人员指出，ApTOLL未显示出与缺血性中风药物产生相互作用，这意味着它可以用于大多数患者。此外，ApTOLL的安全性与耐受性均良好。CYAD-01：公布1期临床试验的初步数据Celyad Oncology公司公布了其在研CAR-T细胞疗法CYAD-01在多种血液系统恶性肿瘤中的早期数据。CYAD-01是一款基于自然杀伤受体NKG2D的自体CAR-T疗法。这是一项开放标签的1期剂量递增试验，针对至少接受过一线治疗的复发/难治性急性髓系白血病（AML）、骨髓增生异常综合征（MDS）和多发性骨髓瘤患者开展。与大多数在研CAR-T细胞疗法的研究不同，该研究在没有任何预处理化疗的情况下，对多次单独输注CYAD-01的治疗方案进行了评估。研究结果显示，CYAD-01的安全性良好，12例可评估的AML/MDS患者中有3例达成客观缓解。值得一提的是，该试验患者的中位年龄较大，一般状况较差。在这些难以治疗的患者群体中的数据为靶向NKG2D配体的候选CAR-T细胞疗法提供概念验证，并支持此类疗法的进一步开发。CELZ-201：启动1/2期临床试验CELZ-201是Creative Medical Technology公司开发的一款细胞疗法，目前正在接受评估，作为新诊断的1型糖尿病（T1D）患者的治疗方法。CELZ-201是一种围产期组织衍生细胞（PRDC）疗法，具有PRDC的可自我更新、低抗原性和低毒性的特点，并能在临床上进行大规模扩增。STAR-0215：启动1b/2期临床试验STAR-0215是Astria Therapeutics公司开发的血浆激肽释放酶单克隆抗体抑制剂，旨在为遗传性血管性水肿（HAE）患者提供长效且有效的预防性治疗选择，设计以每3个月或更长周期给药一次。此前，该公司已公布了STAR-0215在健康受试者中的1a期临床试验的初步数据。结果显示，STAR-0215具有作为长效血浆激肽释放酶抑制剂的潜力，预估半衰期长达110天，支持STAR-0215每三个月给药一次或以更低的频率给药。该公司于近日宣布启动在HAE患者中开展的1b/2期试验。HP518：IND申请获得FDA许可HP518是Hinova Pharmaceuticals公司开发的嵌合降解剂，通过靶向雄激素受体（AR）蛋白以治疗转移性去势抵抗性前列腺癌（mCRPC）。AR是一种经验证的前列腺癌治疗靶点，但AR基因的扩增、突变等多种机制会导致癌细胞对药物不产生应答。HP518通过靶向降解AR蛋白，有望克服由某些特定AR基因突变引起的前列腺癌耐药性。在临床前研究中，HP518对野生型AR和一些对恩杂鲁胺耐药的特定AR突变表现出优异的选择性和降解活性。此外，HP518在异种移植小鼠模型中也展现了出色的抗肿瘤作用。AC0676：IND申请获得FDA许可AC0676是由Accutar Biotechnology通过人工智能（AI）赋能药物发现的口服嵌合降解剂分子，旨在靶向并降解布鲁顿酪氨酸激酶（BTK），有潜力用于治疗复发/难治性B细胞恶性肿瘤。BTK在许多B细胞恶性肿瘤的病理生理学中具有关键作用。与基于共价和非共价作用的BTK抑制剂不同，AC0676能够通过同时去除BTK的激酶和支架作用，为B细胞恶性肿瘤患者提供潜在的新治疗选择。在临床前研究中，AC0676能够选择性地有效降解BTK蛋白，覆盖范围广泛，包括BTK野生型和突变体（包括C481S，L528W等）。此外，AC0676具有良好的药理学特性，在动物模型中也展现出潜在的抗肿瘤活性。ART0380：启动2期临床试验ART0380是Artios Pharma公司针对DNA损伤反应（DDR）所开发的新型小分子抑制剂。此药物靶向ATR——一种DNA复制应激反应的主要调节因子，因此可与导致DNA损伤的药物结合使用，以治疗DNA修复缺陷的癌症。目前，ART0380正在被开发与吉西他滨联用，治疗铂耐药的卵巢癌。1期剂量递增试中，ART0380在晚期实体肿瘤中表现出良好的安全性、耐受性、临床活性和药代动力学特征。该公司在近期已启动了在实体肿瘤中首个2期试验的扩展队列研究，针对铂耐药卵巢癌患者的初步数据预计将在2025年上半年公布。Ziftomenib：启动2期临床试验Ziftomenib是Kura Oncology公司开发的新型口服menin抑制剂，靶向menin-KMT2A/MLL蛋白相互作用，用于治疗NPM1突变型AML。此前，ziftomenib已获得美国FDA授予的孤儿药资格，用于治疗AML。Kura公布的1期临床试验结果显示，截至2022年10月24日的数据，接受600 mg剂量ziftomenib的20例NPM1突变型AML患者中有30%达到了CR。此外，该剂量下ziftomenib的安全性和耐受性良好，被指定为RP2D。该候选疗法的2期试验在近期已完成了首批患者给药。Lucid-MS：获加拿大卫生部批准开展1期试验Lucid-MS是FSD Pharma公司开发的一款潜在“first-in-class”、具神经保护性的化合物，并具创新的治疗机制，用于治疗多发性硬化（MS）。MS是由于免疫系统攻击保护神经的髓鞘而产生的慢性自身免疫性疾病。MS的进展导致身体机能（例如步行）和认知功能（例如记忆）的下降。临床前试验显示，Lucid-MS能够避免髓鞘降解（即脱髓鞘反应），这是造成MS与其他神经退化性疾病的原因。此外，还观察到Lucid-MS能够促进MS实验动物模型的功能性恢复。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲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] Accutar Biotechnology Announces FDA Clearance of IND Application for Phase 1 Trial of AC0676 in B-cell Malignancies. Retrieved February 7, 2023, from https://www.businesswire.com/news/home/20230203005452/en[2] Seelos Therapeutics Doses First Patients in an Ethnobridging Study with SLS-002 (Intranasal Racemic Ketamine). Retrieved February 7, 2023, from https://seelos.irpass.com/profiles/investor/NewsPrint.asp?v=6&b=2376&ID=115640&m=rl&g=1201[3] Hinova Receives FDA Proceed Authorization for its IND Application for HP518, an Orally Bioavailable Chimeric Degrader Targeting Androgen Receptor for Prostate Cancer Treatment. Retrieved February 9, 2023, from https://www.prnewswire.com/news-releases/hinova-receives-fda-proceed-authorization-for-its-ind-application-for-hp518-an-orally-bioavailable-chimeric-degrader-targeting-androgen-receptor-for-prostate-cancer-treatment-301739031.html[4] FSD Pharma Receives Regulatory Clearance for Its Proposed Phase-1 Clinical Trial of Lucid-21-302 (Lucid-MS), First-in-Class Multiple Sclerosis Drug Candidate. Retrieved February 10, 2023, from https://www.businesswire.com/news/home/20230207005742/en/[5] Astria Therapeutics Initiates ALPHA-STAR Phase 1b/2 Clinical Trial of STAR-0215 in People with HAE. Retrieved February 10, 2023, from https://www.businesswire.com/news/home/20230208005071/en/[6] Century Therapeutics Announces First Patient Dosed in First-In-Human Phase 1 ELiPSE-1 Trial Evaluating CNTY-101 in Relapsed or Refractory CD19 Positive B-cell Lymphomas. Retrieved February 10, 2023, from https://investors.centurytx.com/news-releases/news-release-details/century-therapeutics-announces-first-patient-dosed-first-human[7] Creative Medical Technology Holdings Announces IRB Approval for FDA Cleared Phase 1/2 Clinical Trial of Novel Cell Therapy for the Treatment of Type 1 Diabetes. Retrieved February 10, 2023, from https://www.prnewswire.com/news-releases/creative-medical-technology-holdings-announces-irb-approval-for-fda-cleared-phase-12-clinical-trial-of-novel-cell-therapy-for-the-treatment-of-type-1-diabetes-301741094.html[8] Seres Therapeutics Announces Initiation of Enrollment in SER-155 Phase 1b Study Cohort 2 in Individuals Undergoing Allogeneic Hematopoietic Stem Cell Transplantation. Retrieved February 10, 2023, from https://www.businesswire.com/news/home/20230208005144/en/[9] Celyad Oncology announces the publication of data from its Phase 1 THINK study of CYAD-01. Retrieved February 10, 2023, from https://www.globenewswire.com/news-release/2023/02/09/2604573/0/en/Celyad-Oncology-announces-the-publication-of-data-from-its-Phase-1-THINK-study-of-CYAD-01.html[10] Immix Biopharma Subsidiary Nexcella, Inc. Presents 42-Patient Interim Data, with 90% Overall Response Rate in Relapsed or Refractory Multiple Myeloma at NXC-201 Therapeutic Dose from its Phase 1 Expansion Trial at the 5th European CAR T-cell Meeting. Retrieved February 10, 2023, from https://www.globenewswire.com/news-release/2023/02/09/2604948/0/en/Immix-Biopharma-Subsidiary-Nexcella-Inc-Presents-42-Patient-Interim-Data-with-90-Overall-Response-Rate-in-Relapsed-or-Refractory-Multiple-Myeloma-at-NXC-201-Therapeutic-Dose-from-i.html[11] KURA ONCOLOGY ANNOUNCES FIRST PATIENTS DOSED IN PHASE 2 REGISTRATION-DIRECTED TRIAL OF ZIFTOMENIB IN NPM1-MUTANT ACUTE MYELOID LEUKEMIA. Retrieved February 10, 2023, from https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-announces-first-patients-dosed-phase-2[12] aptaTargets’ ApTOLL reduces mortality from 18% to 5% in a Phase 1b/2a trial in ischemic stroke patients. Retrieved February 10, 2023, from https://aptatargets.com/newsroom/aptoll-reduces-mortality-from-18-to-5-in-a-phase-1b-2a-trial-in-ischemic-stroke-patients/[13] Artios Announces Initiation of Phase 2 Randomized Trial for ATR Inhibitor ART0380 plus Gemcitabine in Patients with Platinum Resistant Ovarian Cancer. Retrieved February 10, 2023, from https://www.artios.com/press-release/artios-announces-initiation-of-phase-2-randomized-trial-for-atr-inhibitor-art0380-plus-gemcitabine-in-patients-with-platinum-resistant-ovarian-cancer/[14] Galapagos presented encouraging initial safety and efficacy data at 2023 EBMT-EHA for point-of-care manufactured CAR-T candidate, GLPG5201, in rrCLL. Retrieved February 10, 2023, from https://ml-eu.globenewswire.com/Resource/Download/94396325-2b75-4b81-8100-32aa817771a9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

细胞疗法免疫疗法临床2期临床结果临床1期

2023-02-09

·GlobeNewswire-Health Care

Celyad Oncology announces the publication of data from its Phase 1 THINK study of CYAD-01

MONT-SAINT-GUIBERT, Belgium, Feb. 09, 2023 (GLOBE NEWSWIRE) -- Celyad Oncology (Euronext & Nasdaq: CYAD) (the “Company”), a biotechnology company focused on the discovery and development of innovative technologies for chimeric antigen receptor (CAR) T-cell therapies, today announces the publication of the data from the haematological arm of the THINK study which evaluated CYAD-01 in relapsed or refractory (r/r) acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) or multiple myeloma (MM) patients. The findings were published in the journal The Lancet Haematology. CYAD-01 is the Company’s first autologous CAR T-cell candidate, based on the natural killer receptor NKG2D, assessed clinically. The completed THINK study was an open-label, dose-escalation Phase 1 study for patients with r/r AML, MDS, or MM, after at least one previous line of therapy. Patients were recruited from five hospitals in the USA and Belgium. The Lancet Haematology publication includes data from the 16 patients treated with CYAD-01 in the dose escalation segment of the study, which evaluated three dose levels of CYAD-01 using a schedule of three infusions at two-week intervals in the absence of any preconditioning chemotherapy. Overall, CYAD-01 showed favourable safety data with signs of clinical activity with three of the 12 evaluable AML/MDS patients presenting an objective response. Importantly, the THINK study is one of the first completed dose-escalation CAR T-cell studies in r/r AML/MDS. Unlike the majority of the studies evaluating CAR T-cell therapy candidates, the THINK study evaluated multiple infusions of CYAD-01 as a stand-alone product candidate (i.e., without prior bridging or preconditioning chemotherapy). This feature is of particular interest considering the median older age and the poorer general condition of patients with r/r AML or MDS at diagnosis. Although the need to improve the anti-tumour activity is warranted, these data in a difficult-to-treat patient population potentially provide the proof-of-concept of targeting NKG2D ligands by a CAR T-cell product candidate, and support the further development of NKG2D-based CAR T-cell therapies. About Celyad Oncology Celyad Oncology is a biotechnology company focused on the discovery and development of innovative technologies for chimeric antigen receptor (CAR) T-cell therapies. The Company is focusing on opportunities to fully harness the true potential of its proprietary technology platforms and intellectual property and support the development of next-generation CAR T candidates in solid tumors and hematological malignancies. Celyad Oncology is based in Mont-Saint-Guibert, Belgium and New York, NY. For more information, please visit www.celyad.com. Celyad Oncology Forward-Looking Statement This release may contain forward-looking statements, within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding the potential safety, activity, and feasibility of CYAD-01 cell therapy and other product NKG2D-based candidates or the clinical and commercial potential of these product candidates. The words “potential,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this release are based on management’s current expectations and beliefs and are subject to a number of known and unknown risks, uncertainties and important factors which might cause actual events, results, financial condition, performance or achievements of Celyad Oncology to differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation, risks related to the material uncertainty about the Company’s ability to continue as a going concern; the Company’s ability to realize the expected benefits of its updated strategic business model; the Company’s ability to develop its IP assets and enter into partnerships with outside parties; the Company’s ability to enforce its patents and other IP rights; the possibility that the Company may infringe on the patents or IP rights of others and be required to defend against patent or other IP rights suits; the possibility that the Company may not successfully defend itself against claims of patent infringement or other IP rights suits, which could result in substantial claims for damages against the Company; the possibility that the Company may become involved in lawsuits to protect or enforce its patents, which could be expensive, time-consuming, and unsuccessful; the Company’s ability to protect its IP rights throughout the world; the potential for patents held by the Company to be found invalid or unenforceable; and other risks identified in Celyad Oncology’s U.S. Securities and Exchange Commission (SEC) filings and reports, including in the latest Annual Report on Form 20-F filed with the SEC and subsequent filings and reports by Celyad Oncology. These forward-looking statements speak only as of the date of publication of this document and Celyad Oncology’s actual results may differ materially from those expressed or implied by these forward-looking statements. Celyad Oncology expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based, unless required by law or regulation. Celyad Oncology Contacts: Investor Contact:Media Contact:David GeorgesVP Finance and Administrationinvestors@celyad.comCaroline LonezR&D Communications and Business Developmentcommunications@celyad.com Source: Celyad Oncology SA

细胞疗法临床1期免疫疗法

2022-09-15

·生物制品圈

免疫细胞治疗实体瘤的进展

肿瘤细胞治疗领域非常受关注。去年，一条“120万就能治好肿瘤”的消息引起很大反响。但大家知道，目前为止，无论我们国家还是其他国家批准上市的免疫细胞治疗产品，大多都是针对血液系统肿瘤的。面对这么好的肿瘤攻克技术，实体瘤方面也不能落后。今天给大家介绍的就是在免疫细胞治疗中实体瘤部分的进展，以及遇到的困难和瓶颈，包括我们未来需要克服的问题。1免疫细胞治疗种类以及管线布局随着研究的进展，免疫治疗临床现用的细胞种类非常多。八十年代末，最早进入临床研究的是LAK细胞（淋巴因子激活的杀伤细胞）。另一类耳熟能详的是CIK细胞（细胞因子活化杀伤细胞），目前这个细胞种类仍然在研，比如在德国和意大利国家等国家。在北京一家公司研发的一个类似CIK细胞类型，经试验，在肝癌术后防复发方面疗效非常好，有望很快上市。我经常说细胞是没有罪的，谈到一个具体的细胞类型，只能说在不同的临床条件下适应症是不一样的。现阶段，NK细胞（自然杀伤细胞）是进展非常快的。gdT细胞在我国科学家的带领下，基础和临床转化方面也做了很多很好的工作。实际上，DC（树突状细胞）和CTL（细胞毒性T淋巴细胞）早前被认为是最有希望能解决肿瘤问题的免疫细胞种类。在上世纪九十年代，我攻读博士期间，主要鉴定新型抗原用于疫苗的设计和临床试验，然后分析临床反应和免疫反应。但是做到现在，除了Provenge外还没有一个成熟的产品上市，这其中除了临床问题，还有具体的机制问题。TIL（肿瘤浸润淋巴细胞）这种细胞类型，虽然八十年代就开始在临床应用并报道有效性，但一直到现在还没有上市。由于近年来美国的临床试验证明了其在宫颈癌方面确实是非常好的效果，能使晚期患者的ORR（客观缓解率）达到40%，而常规的大概在10%左右。目前，研究最火热的就是基因修饰的免疫细胞类型，包括TCR-T、CAR-T、CAR-NK等。其中，TCR-T项目国内做的不少的，但遗憾的是到现在没有一个产品获批。主要原因是，受试人群病例筛查的问题、靶点的选择问题，以及因为有HLA限制性所以在临床筛查方面有一定困难。CAR-NK在血液疾病应用方面有效率很好，而且没有严重的CRS副作用，所以也是一个发展方向。但是能不能靠CAR-NK取代CAR-T呢？现有研究认为，免疫细胞中T细胞是杀灭肿瘤的主力军，但NK细胞的重要作用也在越来越凸显出来，有研究认为CAR-T细胞治疗以后，CAR-NK细胞介入后在清除残存肿瘤细胞方面尤为重要方面。先用CAR-T细胞后用CAR-NK细胞，可以更加有效减少细胞治疗副作用、增加疗效和防止复发，我觉得这样的细胞序贯疗法是未来方向之一，但需要更多的临床试验研究来进一步验证。此外，还有我们现在做的用CAR这种类型基因修饰包括TIL，也是未来发展方向。，以及遇到的困难和瓶颈，包括我们未来需要克服的问题。2免疫细胞治疗发展简史简要回顾一下细胞治疗免疫。1985年，LAK细胞就在美国临床试验中出现。应用自体LAK细胞治疗转移性恶性肿瘤，1例患者完全缓解，其客观缓解率44%；1988年，TILs在治疗转移性恶性黑色素瘤方面，可使患者达到60%客观缓解率；2002年，第二代CAR诞生；2006年，开展TCR-T细胞的临床试验证明其有效；2017年，第一个CAR-T细胞治疗的产品被美国批准。中国去年批了两类CAR-T细胞进入临床，这是中国细胞免疫治疗发展史的迎来里程碑事件。从2015年到现在，我们团队主要方向还是做实体肿瘤，同时也做了多种血液肿瘤患者临床研究。CAR-T细胞获批准，主要原因是其CR率很高，白血病患者CR率90%左右，淋巴瘤为50%以上，最重要的是常规的平均长期生存仅为5年，现与之前相比可提高4倍。当然，现在很多的CAR-T细胞治疗，特别血液肿瘤方面，在出现CR以后，后续桥接也是防止复发的重要手段。全球有8个CAR-T细胞产品或适应症获得批准，其中两个产品在我们国家批准上市，但两个技术都是从国外引用的。我们国家自主知识产权CAR-T细胞的技术，只有南京传奇的BCMA靶向BCMA的产品被美国批准了。预计在今年年底或者明年年初，中国或有1-2个细胞治疗产品可以被批准临床应用，这个消息极大地鼓舞人心。如果这时问我，120万元的CAR-T疗法还有没有可能降低，我觉得完全有可能。有一些国内的企业把CAR-T细胞制备成本降的非常低，不难想象，对标PD-1单抗，在2018年以前，其年费可能高达100万，现在进入医保报销以后，个人只需负担几千块钱。CAR-T细胞当然不可能那么便宜，至少说未来的CAR-T细胞成本肯定会大大降低。3CAR-T细胞疗法前沿进展1CAR-T临床热门应用中截止到2022年4月15日，免疫细胞治疗的产品2756种在临床管线中做各种各样的临床试验工作。虽然细胞治疗产品种类非常多，但还是以CAR-T细胞疗法领先。从靶点来说，大家可以看到，针对血液肿瘤仍然是CD19、DCMA、CD22这些常见的靶点。众所周知，实体肿瘤在全部患者中占比90%。在过去几年，大家都专注于在血液肿瘤中的CAR-T应用成功，大家已经开始在讨论CAR-T细胞在实体瘤中的应用。如果攻克哪怕一种实体肿瘤，都会在实体瘤领域有大踏步的进展。沈琳教授开展了靶向Claudin18.2的CAR-T细胞在胃癌中的研究，这是很好的临床试验，经过非常艰辛的靶点的筛查工作，在病人入组方面也有非常严格的限制。这个临床试验给我们实体瘤领域带来了很大的进展对实体瘤临床治疗带来很大鼓舞。从2016年开始，多种CAR-T细胞治疗实体瘤方向均有不同的进展，到目前为止，我们承担了30多个临床试验相关工作。我们用二代CAR-T做的治疗过程中，部分试验结果显示安全性没问题，没有不良事件的发生。仅有部分患者疾病得到了控制，大部分患者效果不理想。尽管这个治疗效果没有达到预期，但是对这些病例的认真研究给我们下一步的改进提供了非常好的方向。2CAR-T治疗限制因素通过这些分析，我们得到了很多有益的提示。主流认为T细胞是核心，这里面T细胞核心就是进不去，杀不了，杀不动，根据这个情况，我应邀写了一篇综述，对CAR-T细胞在实体肿瘤改造策略进行点评。目前针对CAR的改造策略，包括多种不同的改造技术，像如何能够增加CAR-T细胞的扩增，克服CAR-T在肿瘤微环境的抑制问题等。Carl June团队对靶向BSMA的CAR-T细胞表面免疫抑制分子做了一个改造，取得了较好的临床结果，证明四代CAR-T改造将来也有可能带来非常好的结果。（1）进不去问题我们在过去几年为增强肿瘤杀伤细胞向肿瘤部位的浸润，做了包括联合肿瘤病毒、联合趋化因子等工作并已经申报了专利。另外，我们发现CXCR3是T细胞肿瘤微环境至关重要的趋化因子受体。在四代CAR改造中，还在CAR-T方面偶联了CXCR3的配体CXCL9，构建新型的 CAR-T，这种改造明显增加了CAR-T细胞向肿瘤部位的趋化。同时做了一些临床试验，初步证明了四代CAR-T有较好的临床效果。（2）杀不了的问题重点在于克服异质性与肿瘤干细胞，发现重要作用靶点CD276。肿瘤干性也是肿瘤复发耐药的关键因素，我们在前期二代CAR-T临床试验中发现很多耐药和复发的患者，后在体外试验证明没有被CAR-T细胞杀死的肿瘤细胞都是干性细胞。针对这个策略，我们要找到怎么解决用CAR-T细胞可以靶向干性的问题。通过大量的分析，证明了IL24可以很好的诱导肿瘤细胞的凋亡，主要降低肿瘤干细胞的成球性，而成球是干性的一个主要特点，而且可以大大降低了干性相关的基因。同时，我们发现了IL24有非常好的正向促进CAR-T细胞功能作用，降低CAR-T细胞表面负调控分子的表达，基于此我们构建了四代CAR NKG2D-IL24。我们做了动物实验，跟二代CAR-NKG2D相比，四代NKG2D-IL24有效延缓肿瘤增长和防止肿瘤复发，可以明显看到四代CAR-T的优越性。（3）杀不动的问题我们做了大概有四五个改造，包括利用分泌PD-1抗体增加微环境中T细胞活性等。基于此，我们也启动了相关的临床试验正在进行中。3整体解决方案（1）解决空间异质性不同肿瘤细胞的靶点表达不一样。现有的CAR-T细胞、TCR-T细胞，大多都是针对单个靶点或双靶点的，这会导致脱靶等问题。（2）解决时间异质性在肿瘤发展的不同阶段，它的靶点表达也会改变。用肿瘤浸润性淋巴细胞，因这些T细胞表达识别不同肿瘤抗原/MHC复合物的不同T细胞受体，可以很好解决肿瘤的异质性问题，这是我们的出发点。（3）解决肿瘤增强受体肿瘤微环境免疫抑制非常强，我们可以用改造来解决这个问题；还有一个最关键的问题，不管是实体瘤还是血液肿瘤，如果CAR-T细胞不扩增基本就没有效果，因此解决扩增问题是关键的。新格兰医学杂志发表一项试验，证明了CAR-T细胞扩增与临床反应呈正相关性，疗效只和扩增有关。我们在长期的随访中也发现了扩增和患者的长期存活有关系。因此这种为促进T细胞扩增而进行的改造将有助于细胞治疗的效果。4科技成果转化这几年我们从技术到临床、理论到实践，形成了自主知识产权体系，申报的专利30余项，授权的专利10项，成果转让7项。6月份，我们在医院领导的支持下，成功转让了一项转让额超过8000万元的细胞疗法技术。希望这些转让的成果未来对解决实体瘤问题有所帮助。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

免疫疗法细胞疗法抗体疫苗信使RNA

100 项与 CYAD-01(Dartmouth College) 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
骨髓增生性疾病	临床2期	美国	Celyad Oncology SA	2018-09-18
骨髓增生性疾病	临床2期	比利时	Celyad Oncology SA	2018-09-18
急性髓性白血病	临床2期	美国	Celyad Oncology SA	2016-12-01
急性髓性白血病	临床2期	比利时	Celyad Oncology SA	2016-12-01
多发性骨髓瘤	临床2期	美国	Celyad Oncology SA	2016-12-01
多发性骨髓瘤	临床2期	比利时	Celyad Oncology SA	2016-12-01
骨髓增生异常综合征	临床2期	-	Ono Pharmaceutical Co., Ltd.	-
骨髓增生异常综合征	临床2期	-	Celyad Oncology SA	-
骨髓增生异常综合征	临床2期	-	Dartmouth College	-
结肠癌肝转移	临床1期	比利时	Celyad Oncology SA	2017-08-07

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临床结果

适应症

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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


NCT03466320 (Deplethink, ASH2019) 人工标引	临床1期	急性髓性白血病 \| 骨髓增生异常综合征	9	CYAD-01 1x108 cells/inf	顧艱鏇襯憲齋鑰製窪網(窪糧鹽製憲膚遞繭顧鏇) = At DL1,3 patients experienced grade (G) 1 toxicity (cytokine release syndrome or CRS and diarrhea), or G2 CRS ,. One other patient experienced G1 CRS during the second cycle. At DL2, only 1 patient experienced G1 related AEs (diarrhea and CRS) after the first CYAD-01 infusion. Another patient experienced G3 CRS during the second cycle. 憲壓鹹醖壓廠觸觸壓艱 (遞淵鬱壓顧鏇夢淵簾選 )	积极	2019-11-13
NCT03466320 (Deplethink, ASH2019) 人工标引	临床1期	急性髓性白血病 \| 骨髓增生异常综合征	9	CYAD-01 3x108 cells/inf		积极	2019-11-13
NCT03018405 (THINK, GlobeNewswire) 人工标引	临床1期	复发性急性髓细胞白血病 \| 骨髓增生异常综合征	20	CYAD 01	餘廠遞夢築顧壓鹹糧餘(網醖鹹膚壓蓋觸簾鑰獵) = 觸顧窪膚鹹蓋遞壓網遞艱廠鹹獵簾壓鏇鹹鑰淵 (齋蓋網齋願遞醖壓淵壓 ) 更多	积极	2019-06-17
NCT03018405 (ASH2018) 人工标引	临床1期	难治性急性髓细胞白血病	12	CYAD-01	糧糧衊遞衊範夢窪選窪(艱觸蓋築顧夢艱膚製蓋) = 5 pts [in DL-1, one pt experienced G3 lymphopenia and a second pt experienced G4 lymphopenia and G4 pneumonitis in DL-2, one pt experienced G3 lymphopenia and G3 thrombocytopenia and two other pts experienced G3 cytokine release syndrome (CRS)] 選艱淵鹹淵憲簾蓋憲鑰 (鹽範廠製遞襯觸夢遞簾 )	积极	2018-11-29