Axicabtagene Ciloleucel

PiNACLE - H2H will evaluate rondecabtagene autoleucel (ronde-cel) versus investigator’s choice of approved CD19 CAR T-cell therapies in patients with aggressive large B-cell lymphoma receiving treatment in the second line (2L) settingRonde-cel is Lyell’s next-generation, dual-targeting CD19/CD20 CAR T-cell therapy designed to deliver improved complete response rates and longer duration of responses over currently approved CD19 CAR T-cell therapiesSteering Committee of distinguished lymphoma experts established to advise on the design and conduct of this first-of-its-kind CAR T-cell clinical trial SOUTH SAN FRANCISCO, Calif., Sept. 03, 2025 (GLOBE NEWSWIRE) -- Lyell Immunopharma, Inc. (Nasdaq: LYEL), a late-stage clinical company advancing next-generation CAR T-cell therapies for patients with cancer, today announced the initiation of PiNACLE - H2H, a Phase 3 head-to-head CAR T-cell therapy randomized controlled trial and the formation of a Steering Committee of preeminent lymphoma experts. The trial is evaluating rondecabtagene autoleucel (ronde-cel, also known as LYL314) compared to lisocabtagene maraleucel (liso-cel) or axicabtagene ciloleucel (axi-cel) for the treatment of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) receiving treatment in the 2L setting. Ronde-cel is an autologous dual-targeting CD19/CD20 chimeric antigen receptor (CAR) T-cell product candidate with Regenerative Medicine Advanced Therapy (RMAT) and Fast Track designations from the U.S. Food and Drug Administration (FDA) for development in patients with R/R LBCL. Ronde-cel targets B cells that express either CD19, CD20, or both, and is manufactured to produce a product with higher proportions of naïve and central memory T cells – features that are designed to deliver improved complete response rates and durability for patients. “We believe, based on the robust emerging clinical profile demonstrated by ronde-cel in the Phase 1/2 trial, that targeting both CD19 and CD20 with full potency can deliver more complete responses and prolong the duration of remission as compared to the single antigen-targeting CD19 CAR T-cell therapies currently approved for patients with aggressive large B-cell lymphoma,” said David Shook, MD, Lyell’s Chief Medical Officer. “We are delighted to be collaborating with a distinguished group of lymphoma and cell therapy experts on the design and conduct of our ground-breaking head-to-head clinical trial and expect to begin enrolling patients by early 2026.” “Lyell is undertaking a well-designed and innovative Phase 3 trial to provide patients and their physicians with the data needed to demonstrate the potential clinical benefit of ronde-cel, a dual-targeting CD19/CD20 CAR T-cell therapy, over and above that of the currently approved CD19 CAR T-cell therapies,” said Michael Jain, MD, PhD, PiNACLE - H2H Steering Committee member and Immune Cell Therapy Medical Director in the Moffitt Cancer Center Department of Blood and Marrow Transplant and Cellular Immunotherapy. “I am encouraged by the promising data from the Phase 1/2 clinical trial of ronde-cel and believe this innovative cell therapy can improve clinical outcomes for patients.” “Lyell is leading the field with the announcement of the first Phase 3 head-to-head CAR T-cell therapy trial for patients with large B-cell lymphoma,” said Matthew Lunning, DO, PiNACLE - H2H Steering Committee member and Professor in the Division of Hematology/Oncology at the University of Nebraska Medical Center. “We have designed this trial evaluating ronde-cel to include the spectrum of patients who are currently receiving CD19 CAR T-cell therapy in the large B-cell lymphoma setting, as well as to provide the option for treatment in the outpatient setting based on the safety profile observed to date.” Members of the PiNACLE - H2H Steering Committee include: Michael Bishop, MD, Professor of Medicine and Director, Hematology/Oncology Cellular Therapy Program, University of Chicago, Chicago, ILMichael Jain, MD, PhD, Immune Cell Therapy Medical Director in the Moffitt Cancer Center Department of Blood and Marrow Transplant and Cellular Immunotherapy, Tampa, FLManali Kamdar, MD, Associate Professor of Medicine and Hematology and Clinical Director of Lymphoma Services, University of Colorado, Denver, COMatthew Lunning, DO, Professor in the Division of Hematology/Oncology and Medical Director of Cellular Therapy at the University of Nebraska Medical Center, Omaha, NEKrish Patel, MD, Director of Lymphoma Research at Sarah Cannon Research Institute (SCRI), Nashville, TNJason Westin, MD, Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX Lyell is advancing two pivotal trials for patients with R/R LBCL: PiNACLE - H2H is a Phase 3 head-to-head CAR T-cell therapy randomized controlled clinical trial of ronde-cel versus investigator’s choice of either liso-cel or axi-cel in patients with R/R LBCL receiving treatment in the 2L setting. Patients randomized to ronde-cel will be treated with a dose of 100 x 106 CAR T cells. The primary endpoint of the trial is event-free survival. The trial is expected to enroll approximately 400 patients with R/R LBCL, including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma, grade 3B follicular lymphoma, or transformed follicular or transformed mantle cell lymphoma who have not previously received CAR T-cell therapy. Patients may be treated with ronde-cel in either the inpatient or outpatient setting and are required to remain near the treating center for 14 days. Clinical site initiation is underway in the United States and Australia, and the first patient is expected to be enrolled by early 2026.PiNACLE is a single-arm pivotal trial of ronde-cel that is enrolling patients with R/R LBCL receiving treatment in the third- or later-line (3L+) setting. This trial is a seamless expansion of the 3L+ cohort of the Phase 1/2 trial of ronde-cel and is expected to enroll approximately 120 patients. The primary endpoint is overall response rate. About Rondecabtagene Autoleucel (Ronde-cel) Rondecabtagene autoleucel (ronde-cel, also known as LYL314) is a next-generation dual-targeting CD19/CD20 CAR T-cell product candidate designed to increase complete response rates and prolong the duration of the responses as compared to the approved CD19‑targeted CAR T-cell therapies for the treatment of R/R LBCL. Ronde-cel is designed with an ‘OR’ logic gate to target B cells that express either CD19, CD20 or both, each with full potency. Ronde-cel is manufactured to produce a CAR T-cell product with higher proportions of naïve and central memory T cells through a proprietary process that enriches for CD62L-expressing cells. This manufacturing process is designed to generate CAR T cells with enhanced antitumor activity. Ronde-cel has received RMAT designation, as well as Fast Track Designation, from the FDA for the treatment of patients with R/R LBCL in the 3L+ setting. About Lyell Lyell is a late-stage clinical company advancing a pipeline of next-generation CAR T-cell therapies for patients with hematologic malignancies and solid tumors. To realize the potential of cell therapy for cancer, Lyell utilizes a suite of technologies to endow CAR T cells with attributes needed to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical responses, including the ability to resist exhaustion, maintain qualities of durable stemness, and function in the hostile tumor microenvironment. Lyell’s LyFE Manufacturing Center™ has commercial launch capability and can manufacture more than 1,200 CAR T-cell doses at full capacity. To learn more, please visit www.lyell.com. Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding: the potential clinical benefits and therapeutic potential of ronde-cel for patients with R/R LBCL, including its potential to increase complete response rates and prolong the duration of responses as compared to approved CD19-targeted CAR T-cell therapies for the treatment of LBCL; the potential benefits, if any, from the RMAT and Fast Track designations from the FDA for the treatment of patients with R/R LBCL in the 3L+ setting; statements made by our Chief Medical Officer and members of the PiNACLE – H2H Steering Committee; expectations around enrollment, trial design, dosing and timing of -PiNACLE and PiNACLE H2H; the sufficiency of the capacity of LyFE to manufacture drug supply for Lyell’s ongoing and planned pivotal trials and through potential commercial launch; and other statements that are not historical fact. These statements are based on Lyell’s current plans, objectives, estimates, expectations and intentions, are not guarantees of future performance and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, but are not limited to, risks and uncertainties related to: the potential for results from clinical trials to differ from nonclinical, early clinical, preliminary or expected results; Lyell’s limited experience as a company in enrolling and conducting clinical trials and lack of experience in completing clinical trials; significant adverse events, toxicities or other undesirable side effects associated with Lyell’s product candidates; Lyell’s ability to initiate or progress clinical trials on the anticipated timelines, if at all; RMAT and Fast Track designations may not actually lead to faster development, regulatory review or approval process, and does not assure ultimate FDA approval; the significant uncertainty associated with Lyell’s product candidates ever receiving any regulatory approvals; Lyell’s ability to obtain, maintain or protect intellectual property rights related to its product candidates; the complexity of manufacturing cellular therapies and Lyell’s ability to manufacture and supply its product candidates for its clinical trials; implementation of Lyell’s strategic plans for its business and product candidates; the sufficiency of Lyell’s capital resources and need for additional capital to achieve its goals; the effects of macroeconomic conditions, including the effects of disruption between the U.S. and its trading partners due to tariffs or other policies, and any geopolitical instability; potential changes to U.S. drug pricing, including the potential for “most-favored nations” pricing limitations; and other risks, including general economic conditions and regulatory developments, not within our control; and other risks described under the heading “Risk Factors” in Lyell’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2025, filed with the Securities and Exchange Commission on August 12, 2025. Forward-looking statements contained in this press release are made as of this date, and Lyell undertakes no duty to update such information except as required under applicable law. Contact: Ellen Rose Senior Vice President, Communications and Investor Relations erose@lyell.com

自体嵌合抗原受体（CAR）T 细胞疗法已彻底改变难治/复发性 B 细胞癌症（急性淋巴细胞白血病、大B细胞淋巴瘤LBCL、骨髓瘤）的治疗，目前美国FDA已批准7款CAR-T细胞产品，同时正探索用于血液系统恶性肿瘤早期治疗、实体瘤及自身免疫病。 传统制造流程和周期 o   起始材料获取：患者白细胞分离术（获取 CD4 + 辅助 T 细胞和 CD8+ 细胞毒性 T 细胞） o   实验室制备：T 细胞富集→激活→CAR 基因转导→体外扩增（1-3 周）→配方→冷冻保存 o   质量控制与交付：质量控制分析（7-15 天）→认证→转运至临床站点 Figure 1: CAR T cell manufacturing work flows 传统制造存在的主要问题 o   患者流失率高：平均静脉到静脉时间 3-6 周，Schuster 等研究显示33% 接受白细胞分离术的 LBCL 患者无法完成 CAR T 细胞输注（因疾病进展）。 o   产品质量不足：部分患者治疗无响应或复发，除基础疾病外，CAR T 细胞产品自身质量是关键,长期体外培养优先 T 细胞扩增而非活性，导致产品植入、体内扩增和持久性不佳，且易出现高分化、耗竭表型。 1、起始材料获取的优化策略 1.  白细胞分离术的个性化改进：O’Reilly 等开发算法，基于白细胞分离术前血液指标（如淋巴细胞计数）预测患者所需分离时间，实现 “个性化采集”，缩短不必要的分离时长，增加每日分离次数，提升设备容量。 2.  外周血替代方案：随着 T 细胞激活和扩增技术进步，可无需白细胞分离术，直接用外周血作为起始材料。研究显示，从健康供体单次抽取50mL外周血即可成功制造 CAR T细胞，虽需患者（尤其经多线治疗者）验证，但有望大幅提升疗法可及性。 2、细胞选择与体外培养的优化  细胞亚型选择：优先低分化 T 细胞 1.  关键 T 细胞亚型特性：低分化 T 细胞（naive T细胞(TN)、干细胞记忆T细胞(TSCM)、中央记忆 T 细胞TCM)）比效应T细胞（(TEM)/(TE)/(TEMRA)）具有更高的增殖能力和细胞因子分泌潜力，且与临床响应和CAR-T细胞持久性相关。 2.  临床研究数据：不同 T 细胞亚型选择的临床效果如下表所示： 3.   挑战：低分化 T 细胞（如(TSCM)）在经多线治疗患者中频率低，且选择过程成本高、需额外体外操作，可能难以达到目标剂量。 体外培养条件优化 1.  培养基成分调整：常规用 CD3/CD28 激活+IL-2 扩增易导致 T 细胞分化，目前优先使用IL-7和IL-15，可防止分化；补充IL-21能进一步富集低分化表型，提升体内疗效。 2.  信号通路调控 o   用 PI3K-AKT 通路抑制剂（如 AKT 抑制剂），可制造出(TSCM)或\(TCM)富集的CAR T细胞，在白血病临床前模型中显示更优抗肿瘤活性，目前已用于 UCL的制造流程（NCT04795882）。 o   酪氨酸激酶抑制剂达沙替尼可可逆抑制CAR信号激酶，预防/逆转因持续激活或无效信号导致的T细胞耗竭，正用于临床制造优化。 3.  工程化细胞因子分泌:CAR-T细胞工程化改造为分泌免疫刺激细胞因子，如 IL-18（NCT04684563）、IL-15，临床显示低剂量（如IL-15分泌型GCP3-CAR T细胞剂量3×107cells/m²）即可实现高扩增和临床响应。 3、制造流程加速：缩短/无扩增方案 （1）核心逻辑 长期体外培养（9 天以上）会损害 T 细胞表型和功能，缩短或省略扩增步骤可保留低分化表型，同时缩短静脉到静脉时间，让更多患者能接受治疗。 （2）临床应用的快速制造方案 不同快速制造产品与传统方案的对比见下表： 产品名称 靶点 制造方案 制造周期 剂量范围 总响应率ORR 完全缓解CR ≥3 级 CRS Axicabtagene ciloleucel（Kite） CD19 传统方案 3-6 周 - - - - Axicabtagene ciloleucel（Kite） CD19 缩短方案 5 天 - 与传统方案相当 与传统方案相当 - Orvacabtagene autoleucel BCMA 传统方案 - 3-6×10⁸ cells 91% 39%（51 例中 20 例） 2%（51 例中 1 例） BMS-986354（BMS） BCMA NEX-T 缩短方案 5-6 天 20-80×10⁶ cells 98.1% 30%（54 例中 16 例） 2%（54 例中 1 例） Tisagenlecleucel（Novartis） CD19 传统方案 - 中位 3.0×10⁸ cells 52% 32%（93 例中 30 例） 22%（111 例中 24 例） YTB323（Novartis） CD19 T-Charge 缩短方案 48h 2.5-12.5×10⁶ cells 73%（剂量 12.5×10⁶） 73%（15 例中 11 例） 6%（16 例中 1 例） F-CAR（Gracell） CD19 无扩增方案 22-36h 3.0-15.6×10⁴ cells/kg 92%（25 例中 23 例） 92%（25 例中 23 例） 24%（25 例中 6 例） （3）无激活方案 传统制造中T细胞激活是为提升病毒转导效率，但激活会触发分化。目前研究通过优化培养容器表面积/体积比、添加核苷、阻断抗病毒感染相关酶，实现无激活状态下的稳定转导，临床前模型（免疫缺陷 B 细胞白血病小鼠）显示可实现持久疾病控制，但临床可行性仍需验证。 4、质量控制和放行的简化 1.传统质控瓶颈：常规无菌检测（培养法）需7-14天，导致产品制造完成后仍需等待 2 周才能释放；CAR 表达检测易受非整合序列和假转导干扰，纸质批记录审核效率低。 2.  优化措施： o   快速无菌检测：采用 PCR-based 检测（如 Microsart®），1 小时内可完成；结合机器学习的长读长测序（16S/18S 扩增子），检测限低至 10 CFU/mL。 o   CAR 表达检测：部分快速方案（如 F-CAR）在冷冻保存后培养 3 天再检测，避免假阳性。 o   认证流程：用电子批记录系统替代纸质记录，符合 21 CFR part 11，提升效率并减少错误。 3.  监管需求：需证明快速检测方法与传统方法性能一致，并调整监管框架，才能广泛应用。 5、床旁制造与体内制造 床旁制造（Point-of-Care） 1.  优势：避免中心化制造的复杂物流，静脉到静脉时间缩短至7-14天，且新鲜输注产品比冷冻产品扩增更好（如Shah等研究中新鲜产品ORR 93%vs冷冻产品 57%）。 2.  临床案例： o   CliniMACS Prodigy 平台：用于 LV20.19（CD19/CD20 双靶点）制造，14 天静脉到静脉时间，85% 患者达到目标剂量，ORR 82%（22 例中 18 例），目前开展多中心II期试验（Daly-2-USA/EU）。 o   GLPG5101：7天静脉到静脉时间，ORR 85%（13例中 11 例），CR69%（13 例中 9 例），产品保留记忆表型。 3.  挑战：需专业团队、多中心制造标准化（如统一检测试剂盒）、监管框架明确，需政府投资和监管调整。 体内制造 1.  技术路径： o   靶向 T 细胞的慢病毒载体：如靶向 CD8α、CD4、CD7 的慢病毒（如 INT2104，NCT06539338），小鼠模型显示可诱导CAR表达、肿瘤杀伤，非人类灵长类显示B细胞耗竭。 o   mRNA/DNA 脂质纳米颗粒（LNP）：用抗 CD3 抗体修饰LNP，靶向递送 CAR mRNA，小鼠模型显示单次给药即可快速清除肿瘤并维持CAR表达。 o   包膜递送载体（EDV）：表达抗 CD3/CD4/CD28单链抗体，可靶向激活 T 细胞并递送CAR基因，人类化小鼠模型显示有效编辑。 2.  挑战：需解决脱靶基因递送（非目标细胞转导）和病毒被宿主免疫清除（尤其非淋巴耗竭患者）的问题，需建立新的质量标准和监管框架。 当前CAR-T制造优化聚焦 “加速流程、提升产品质量”，通过起始材料改进、低分化细胞选择、快速制造方案、床旁制造等策略，已在临床中验证有效性（如低剂量高响应、短周期少患者流失）；未来需推进多中心床旁制造标准化、解决体内制造安全性问题，并通过监管调整和技术创新，让更多患者获得有效治疗。 参考文献：Giulia Agliardi et.al.Accelerating and optimising CAR T-cell manufacture to  deliver better patient products. www.thelancet.com/haematology Published online November 4, 2024 https://doi.org/10.1016/S2352-3026(24)00273-4 识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！ 请注明：姓名+研究方向！ 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。