The liver is both a central metabolic organ and a uniquely tolerogenic immune niche, which makes it a frequent site of liver metastases (LMS) and a challenging environment for immunotherapy. It is increasingly appreciated that resident liver cells- Kupffer cells, Ito cells, liver sinusoidal endothelial cells - as well as infiltrating myeloid and lymphoid populations, collectively establish an immunosuppressive microenvironment that favors metastatic seeding and progression. Advances in our understanding of these cell-cell interactions and the exclusion of effector T cells, have highlighted new therapeutic entry points. In parallel, innovations in gene-delivery platforms, from lentiviral and AAV vectors to lipid nanoparticles, and in engineered immune cells such as CAR-T and CAR-NK cells, are opening avenues to modulate the hepatic tumor niche. Here we review how these insights into liver immunobiology inform the design of next-generation immunotherapies for LMS, emphasizing opportunities and challenges in translating them to the clinic.

2026-02-01·Clinical Nutrition ESPEN

A single-centre retrospective study investigating changes in nutritional status and use of dietetic interventions in children receiving chimeric antigen receptor T-cell therapy

Article

作者: Evans, James ; Chowdhury, Anisah

BACKGROUND AND AIMS:

Chimeric antigen receptor T-cell therapy (CAR-T) is a novel treatment for children with relapsed or refractory acute lymphoblastic leukaemia. Preferential outcomes have been shown when children maintain their nutritional status during cancer treatment. Few studies have investigated the impact of CAR-T on the nutritional status of children. This study aimed to examine the nutritional status and use of dietetic interventions in children having CAR-T.

METHODS:

Electronic records of all children who had CAR-T between June 2015-June 2024 at Great Ormond Street Hospital in London were retrospectively reviewed. Nutritional outcomes were examined during the child's admission for CAR-T, including weight change and dietetic interventions used including oral nutritional supplements, enteral tube feeding and parenteral nutrition. Impact of different interventions on children's weight change and length of stay were analysed.

RESULTS:

CAR-T was provided to 132 children, 65 % male, mean age eight years. Weight change from CAR T-cell infusion to discharge was a mean loss of -1.8 %. Sixty two percent required a dietetic intervention and of these 45 % received oral nutritional supplements, 56 % enteral tube feeding (of these 87 % had a nasogastric tube, 13 % a gastrostomy), 34 % parenteral nutrition. The latter was initiated primarily for intolerance to tube feeding and provided for a mean 23 days. Children who received any dietetic intervention gained more weight than those who received none (+0.7 % v -1.6 %, p = 0.020), as did those who initiated oral nutritional supplements proactively (before day three post-CAR T-cell infusion) versus reactively (on or after day three) (+0.4 % v -3.3 %, p = 0.030), and those who started tube feeding proactively versus reactively (+2.4 % v -3.6 %, p = 0.027). Length of stay was shorter for children who did not receive any dietetic intervention than those who did (19 days v 30, p < 0.001), and those who did not receive tube feeding versus those who did (22 v 32 days, p = 0.001).

CONCLUSION:

Although children experienced a modest weight loss the majority required a dietetic intervention to support this, most commonly oral nutritional supplements and tube feeding. Proactive preparation of families for tube feeding is essential to facilitate acceptance. Children who did not receive a dietetic intervention may have benefitted from dietetic input. With growing evidence of changes in nutritional status and impact on outcomes, dietetic input is key to develop nutritional support algorithms that guide the use of screening, assessment and interventions in children having CAR-T.

2026-02-01·CYTOTHERAPY

Prognostic factors and outcomes of tisagenlecleucel in relapsed or refractory B-cell malignancies: a single-center real-world study

Article

作者: Kim, Yonggoo ; Min, Gi June ; Eom, Ki-Seong ; Lee, Soo Jung ; Park, Sung-Soo ; Jeon, Youngwoo ; Cho, Seok-Goo ; Chung, Nack-Gyun ; Min, Chang-Ki ; Lee, Jae Wook ; Jekarl, Dong Wook ; Yoon, Jae-Ho ; Yoo, Jae Won

BACKGROUND:

Tisagenlecleucel (tisa-cel), a CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy, is an approved treatment for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and B-cell precursor acute lymphoblastic leukemia (B-ALL). While pivotal trials demonstrated its efficacy, real-world evidence from Asian populations remains scarce. In particular, data on manufacturing feasibility, clinical outcomes, and predictive biomarkers in Korean patients are limited.

OBJECTIVE:

This study aimed to evaluate the clinical outcomes and prognostic factors of tisa-cel therapy in Korean patients with R/R DLBCL and B-ALL, with a specific focus on apheresis product quality and baseline immune markers.

STUDY DESIGN:

A single-center retrospective study was conducted including 91 patients (DLBCL = 72; B-ALL = 19) intended to receive tisa-cel between April 2022 and April 2024. Apheresis data, treatment responses, survival outcomes, and toxicity profiles were analyzed. The intention-to-treat (ITT) cohort was defined from the time of apheresis. Cox regression was used to identify predictors of survival and relapse, and separate analyses were performed for DLBCL and B-ALL.

RESULTS:

Out of 91 patients, 72 received tisa-cel infusion. One-year overall survival (OS) and disease-free survival (DFS) for the entire ITT cohort were 45.9% and 37.5%, respectively. In 19 B-ALL after tisa-cel infusion, 1-year OS and DFS were 68.4% and 52.6%, with no non-relapse mortality (NRM). In 53 DLBCL after tisa-cel infusion, 1-year OS and DFS were 46.8% and 41.6%, respectively, with 29.6% cumulative incidence of relapse among responders. NRM was 9.5% mostly observed in elderly patients. In the DLBCL subgroup, poor OS was independently associated with third-or-later-line salvage therapy (hazard ratio [HR] 2.39), high peripheral blood monocyte proportion at apheresis (>10%, HR 2.57), low CD3+ T-cell concentration in apheresis product (<1.0×10⁸/mL, HR 4.31), and occurrence of immune effector cell-associated neurotoxicity syndrome (HR 2.47). B-ALL patients demonstrated favorable survival and lower toxicity, but no significant prognostic markers were identified.

CONCLUSIONS:

Tisa-cel therapy was feasible and effective in Korean patients with R/R B-cell malignancies. Pre-treatment immune parameters such as monocyte burden and CD3+ T-cell quality in apheresis products significantly influenced outcomes in DLBCL. These findings suggest that optimizing patient selection and refining manufacturing strategies may enhance CAR-T efficacy, particularly in resource-constrained or heterogeneous real-world settings.

项与 Cocaine and amphetamine-regulated transcript(Nankai University) 相关的新闻（医药）

2025-12-19

·Illumina因美纳

单细胞“透视”血液肿瘤：端到端方案开启精准诊疗新维度

血液肿瘤作为一类起源于造血系统或淋巴系统的恶性疾病，涵盖白血病、淋巴瘤、骨髓瘤等多个亚型，其诊疗过程长期面临分型模糊、治疗响应不佳、耐药复发率高等核心难题。传统检测技术难以捕获细胞异质性与分子层面的动态变化，导致精准诊疗举步维艰。近年来，单细胞测序技术的崛起为血液肿瘤研究带来革命性突破，尤其是端到端单细胞测序方案凭借高分辨率、高通量的优势，在肿瘤分型、治疗优化、耐药机制解析等方面展现出巨大潜力。本文结合最新研究成果，深度解析单细胞测序在血液肿瘤诊疗中的应用价值与发展前景。血液肿瘤临床诊疗的现实困境当前血液肿瘤临床诊疗面临三大困境，首先其分型复杂，精准诊断难度大，像急性髓系白血病（AML）、急性淋巴细胞白血病（ALL）、多发性骨髓瘤（MM）等血液肿瘤亚型繁多且高度异质，传统分型方法存在局限性，罕见亚型或混合型易混淆诊断，且无法全面覆盖分子标志物，导致临床常因分型不准出现部分患者疗效不佳。其次CAR-T治疗瓶颈待突破，该疗法虽为复发难治性患者带来希望，但在AML等疾病中因缺乏特异性肿瘤抗原靶点、肿瘤微环境影响细胞活性及存在细胞因子风暴等安全性问题应用受限。最后，血液肿瘤耐药与复发机制不明，肿瘤细胞可通过基因变异，转录可塑性等多种方式逃避药物攻击，而传统技术难以捕获稀少耐药细胞亚群的分子特征，如AML患者化疗后残留的干细胞样肿瘤细胞。单细胞测序：血液肿瘤诊疗的技术革新单细胞测序技术打破了传统测序“平均化” 的局限，能够在单个细胞水平上，无偏倚地分析解析基因表达、基因突变、染色质可及性等多维度分子信息，为血液肿瘤研究提供全新视角。其核心优势体现在以下三个方面：一高分辨率的细胞异质性分析血液肿瘤并非由单一类型的细胞组成，而是由多种细胞亚群构成的复杂生态系统。这些不同的细胞亚群在生物学特性和功能上存在显著差异。单细胞测序技术以其高分辨率的优势，能够对单个细胞进行精细的测序分析，从而深入揭示细胞之间的异质性。通过全面分析单个细胞的基因表达谱、基因组变异和表观遗传修饰等多维度信息，单细胞测序技术可以精确地识别出不同的细胞亚群，并深入探究它们在肿瘤发生发展过程中的关键作用。以AML为例，研究发现AML中存在一群具有干细胞特性的白血病细胞，这些细胞不仅具有更强的自我更新能力，还表现出较高的耐药性，是导致疾病复发的关键因素[1]。单细胞测序技术可以精准地分离和分析这些干细胞亚群，为靶向治疗提供有力依据，从而有望改善AML的治疗效果和患者预后。二全面的基因组和转录组分析单细胞测序技术的一大优势在于其能够同时对基因组和转录组进行分析，从而提供全面且深入的分子信息。目前单细胞RNA测序技术相对成熟，在单细胞RNA测序的数据中能够检测单个细胞的基因突变、获得拷贝数变异和染色体结构异常等多种变异类型的评估。这些基因组变异是血液肿瘤发生发展的基础，同时也对治疗反应产生重要影响。例如，TP53基因突变在AML中较为常见，且与预后不良密切相关。单细胞测序技术可以精准地检测出TP53突变的细胞亚群及其在肿瘤中的分布情况，为临床治疗决策提供关键信息[2]。在转录组水平上，单细胞测序技术能够揭示单个细胞的基因表达谱，从而发现新的生物标志物和治疗靶点。如受体酪氨酸激酶家族成员ROR1，其在多种血液恶性肿瘤中呈异常过表达状态，与肿瘤的发生、发展以及耐药性密切相关，单细胞测序技术通过锁定⾼表达ROR1的细胞群体及相关调控通路，为临床开发靶向药物、评估治疗效果提供了关键分子线索[3]。三动态监测肿瘤细胞的演化血液肿瘤在治疗过程中会发生动态变化，肿瘤细胞会通过适应性进化来逃避药物的压力。单细胞测序技术可以动态监测肿瘤细胞的演化过程，深入了解耐药细胞的起源和演化路径。通过对不同治疗时间点的单细胞测序分析，可以发现耐药细胞的基因组和转录组特征，并揭示其耐药机制。例如，在慢性髓性白血病中，单细胞测序技术发现耐药细胞往往具有特定的基因突变和基因表达谱，这些特征可以作为预测耐药和优化治疗方案的依据[4]。此外，单细胞测序技术还可以用于监测肿瘤细胞在体内的分布和转移情况，为疾病的早期诊断和治疗提供重要信息，有助于实现对血液肿瘤的精准监测和个性化治疗。单细胞测序在血液肿瘤中的三大应用场景一高精度分型，指导精准用药传统分型无法区分同一患者中不同恶性克隆的分子特征，而单细胞测序通过对骨髓或外周血样本进行全景式分析，可精确识别具有不同生物学行为的细胞亚群，为个体化治疗提供核心指导。这⼀技术优势已在多项权威研究中得到证实，并推动血液肿瘤诊疗向精准化迈进。《Nature Medicine》的一项研究通过对千余名AML患者数据构建单细胞参考图谱，揭示了白血病细胞的层次结构，并建立了与化疗及靶向治疗反应相关的分子分型新框架[5]。类似地，在MM领域，《Haematologica》的研究通过单细胞技术明确，IgD型MM在转录组、免疫组及肿瘤微环境层面均与其他亚型存在显著差异，且更适合来那度胺联合维奈克拉方案，而需谨慎使用硼替佐米[6]。这种精准分型不仅提升了临床诊断效率，更直接优化了治疗方案的选择。Mehmet等人发表于《Blood》的综述则进一步指出，单细胞分析为理解MM克隆进化、转录重编程、耐药机制及微环境特征提供了关键认知，这些发现正逐步转化为临床实践（图1）[7]。图1 使用来自骨髓、血液或骨髓外病变的细胞以及单细胞平台来验证各种假说的研究概念总览进一步而言，单细胞技术的价值不仅在于描述细胞状态，更在于解析基因调控的功能机制。例如，Greenwood等人采用eCROPseq（单细胞CRISPR筛选结合RNA测序）技术，在人类髓系细胞中实现了单细胞水平的功能基因组学筛选。该研究证实，许多基因表达调控信号并非由单一变异驱动，而是由多个SNP构成的单倍型共同作用[8]。这一发现揭示了血液肿瘤遗传调控的深层复杂性，提示仅关注单一“热点”突变可能不足以完全阐释疾病机制。然而，此类功能筛选技术通常依赖体外细胞培养与病毒转导，对原代肿瘤细胞——尤其是稀有干细胞亚群——损伤显著、存活率低，易造成关键生物学信息丢失。对此，Illumina Single Cell Prep（ISCP）建库方案展现出独特优势：其灵活、温和的样本处理流程，特别是针对细胞核测序的优化，可直接分析冻存或难处理的骨髓样本，最大限度降低细胞损伤，高效捕获包括稀有干细胞在内的更多种类的细胞亚群。不仅如此，未来将上市的Illumina Single Cell CRISPR Prep可在百万细胞量级上直接识别CRISPR sgRNA骨架序列，实现mRNA与gRNA的双重捕获。另外ISCP具有低多胞率的特征，减少了CRISPR结合单细胞测序特有的数据分析挑战。凭借增强的单次检测高达100万细胞级别的可扩展性、无需额外昂贵设备的简化工作流程、与基因测序仪的无缝集成、更低成本以及高度灵活的实验设计，ISCP结合CRISPR技术将有力推动功能筛选研究，促进功能性发现向临床价值的快速转化。二解析CAR-T细胞状态，优化免疫治疗 CAR-T疗法在AML等髓系血液肿瘤中疗效有限，其瓶颈之一在于难以动态掌握CAR-T细胞在体内的功能状态、耗竭轨迹及其与肿瘤微环境的相互作用。单细胞组学能够动态解析CAR-T细胞在体内的功能状态、异质性及其与肿瘤微环境的复杂互作，帮助识别与疗效密切相关的关键细胞亚群和调控机制，从而为CAR-T疗法的优化和个体化免疫治疗策略提供科学依据。Navin Varadarajan团队在《Nature Cancer》上的一项研究通过包含单细胞组学在内的多组学动态分析，揭示了弥漫性大B细胞淋巴瘤患者中CD19特异性CAR-T细胞的异质性。研究整合了细胞的功能、表型、转录谱和代谢特征，最终确定并验证了一个称为CD8-fit T细胞的亚群，该亚群与CAR-T治疗的临床效果密切相关（图2）[9]。图2 CD8-fit的分子谱与单细胞RNA测序揭示的临床反应相关。此外，肿瘤微环境中的髓系细胞等组分也可能通过细胞特异性信号影响CAR-T功能。正如Greenwood等人所示，同一基因在不同髓系细胞中编辑可产生迥异的表达效应[8]，提示TME的细胞构成对治疗响应具有调控潜力。然而，全面绘制CAR-T与TME的互作网络，需捕获包括稀有免疫细胞在内的全部组分，传统单细胞方案在通量灵活性上存在限制，难以兼顾成本与细胞覆盖度。ISCP测序方案凭借其灵活通量设计，可支持在早期筛选阶段采用低通量进行经济、快速的功能验证；在深入机制阶段则转为高通量模式，实现对全TME细胞群体的深度测绘。这种“可伸缩”的通量策略，使CAR-T研究与临床转化更高效、更具性价比。三追踪细胞演化轨迹，揭示耐药机制肿瘤耐药与复发通常由少数细胞亚群在药物压力下通过适应性进化驱动，传统批量测序难以捕捉此类动态过程。单细胞技术则能够高分辨率地“回放”细胞演化轨迹，识别耐药亚群并解析其分子基础。例如，《Nature Cancer》上一项针对T-ALL的研究通过对40例T-ALL患者的单细胞多组学分析，结合健康儿童造血发育图谱，成功构建了一个多组学图谱。研究通过轨迹分析发现了一种类似于骨髓祖细胞（BMP）的白血病亚群，与治疗失败和预后不良密切相关。该亚群的分子标志物能够预测多种T-ALL亚型的不良结果，并揭示了NOTCH1突变在推动T-ALL细胞远离BMP样状态中的作用。此外，通过计算机模拟和体外药物筛选，研究团队还发现了针对BMP样细胞的潜在治疗靶点，包括BCL-2抑制剂维奈托克。这些发现进一步证实了BMP样细胞的耐药性，并为T-ALL开发新的精准治疗策略提供了新的思路潜在靶点（图3）[10]。图3 参照人类造血，T-ALL亚型的停滞状态另外，《Nature Communication》上的一项研究通过单细胞转录组测序，系统描绘了AML患者对BCL-2抑制剂venetoclax的原发性和获得性耐药情况。研究整合13例患者样本，利用拟时序分析重建耐药演化轨迹，发现CD36高表达与氧化磷酸化通路激活是耐药核心机制[11]。单细胞轨迹推断显示，耐药细胞沿代谢重编程路径演化，从糖酵解依赖转向脂肪酸氧化供能,该发现揭示了代谢可塑性在耐药中的驱动作用，为联合靶向代谢通路克服耐药提供了理论依据。精准追踪细胞演化路径依赖高质量的全转录本信息，而传统液滴式单细胞技术因mRNA捕获效率受限，对长转录本及低丰度基因检出灵敏度不足，可能导致关键分子事件遗漏。相较之下，ISCP单细胞建库方案采用更温和的细胞捕获策略，能够覆盖更完整的细胞亚型谱系，结合轨迹分析可构建更清晰准确的细胞演化图景，为深入解析细胞演化驱动的耐药机制提供了稳健可靠的技术平台。多组学联合：单细胞测序的未来方向血液肿瘤诊疗正从“经验医学”向“精准医学”转型，单细胞测序技术凭借其高分辨率、无偏倚和高通量优势，在肿瘤异质性解析、治疗策略优化和耐药机制探索中展现出重要价值。然而，技术发展的下一阶段，其价值不仅在于“看得更细”，更在于“看得更透”。通过整合单细胞转录组与空间定位、表观遗传、蛋白表达等多维信息，能够系统构建疾病的动态全景视图。这种多组学融合的研究策略，超越了单一的细胞图谱，真正揭示了肿瘤细胞在特定微环境中的动态演变，以及其与免疫细胞和基质细胞之间的复杂相互作用。最终为精准诊断和个性化治疗方案的制定提供了更为坚实和全面的科学依据。在这一技术演进过程中，Illumina单细胞全流程服务为研究者提供了系统化的支持： 01 强大的可拓展性：核心单细胞技术能够与空间生物学、表观遗传学等多组学方案无缝衔接，满足从基础研究到临床验证的多样化需求。 02 便捷的数据分析：借助DRAGEN服务器的强大分析能力和Illumina Connected Multiomics （ICM）软件的直观界面，即使是非生物信息学背景的用户，也能轻松完成从原始数据到可视化结果的完整分析。 03 灵活的方案设计：支持从大队列图谱构建到精细化机制探索的各类研究设计，提供高效且经济的个性化解决方案。展望未来，单细胞多组学技术正在重塑我们对血液肿瘤生物学的理解，推动研究范式从“群体平均”向“细胞精准”转变。以Illumina为代表的集成化技术平台，为从细胞层面的洞察向临床诊疗策略的转化提供了关键工具。这些技术不仅加速了基础研究的突破，更为临床应用提供了切实可行的路径，有望在未来进一步提升血液肿瘤的精准诊疗水平，改善患者的治疗效果和生活质量。参考文献：（滑动查看） 1.Ma X, Li Y, Wang D, Niu J, Li Q, Chen Y, Wang M, Wen J, Liao C, Wang N, Zhang X, Chang J, Yang J, Li L, Zou J, Peng D, Liu L. PSMB10 maintains the stemness of chemotherapeutic drug-resistant leukemia cells by inhibiting senescence and cytotoxic T lymphocyte-mediated killing in a ubiquitinated degradation manner. J Exp Clin Cancer Res. 2025 Jun 3;44(1):170. doi: 10.1186/s13046-025-03420-9. PMID: 40462177. 2.Semba Y, Yamauchi T, Bauer DE, Ogawa S, Akashi K, Maeda T. The XPO7-NPAT axis represents key vulnerabilities in TP53-mutated acute myeloid leukemia. Blood. 2025 Oct 29:blood.2025028918. doi: 10.1182/blood.2025028918. Epub ahead of print. PMID: 41160778. 3.Tigu AB, Munteanu R, Moldovan C, Rares D, Kegyes D, Tomai R, Moisoiu V, Ghiaur G, Tomuleasa C, Einsele H, Gulei D, Croce CM. Therapeutic advances in the targeting of ROR1 in hematological cancers. Cell Death Discov. 2024 Nov 17;10(1):471. doi: 10.1038/s41420-024-02239-1. PMID: 39551787. 4.Krishnan V, Schmidt F, Nawaz Z, Venkatesh PN, Lee KL, Ren X, Chan ZE, Yu M, Makheja M, Rayan NA, Lim MGL, Cheung AMS, Bari S, Chng WJ, Than H, Ouyang J, Rackham O, Tan TZ, Hwang WYK, Chuah C, Prabhakar S, Ong ST. A single-cell atlas identifies pretreatment features of primary imatinib resistance in chronic myeloid leukemia. Blood. 2023 Jun 1;141(22):2738-2755. doi: 10.1182/blood.2022017295. PMID: 36857629. 5.Zeng AGX, Bansal S, Jin L, et al. A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia. Nat Med. 2022 Jun;28(6):1212-1223. doi: 10.1038/s41591-022-01819-x. Epub 2022 May 26. PMID: 35618837. 6.Luo T, Zhou X, Chen X, et al. Single-cell analysis unveils distinct transcriptional alterations and cellular origins in IgD multiple myeloma. Haematologica. 2025 Oct 30. doi: 10.3324/haematol.2025.288418. Epub ahead of print. PMID: 41163585. 7.Samur MK, Szalat R, Munshi NC. Single-cell profiling in multiple myeloma: insights, problems, and promises. Blood. 2023 Jul 27;142(4):313-324. doi: 10.1182/blood.2022017145. PMID: 37196627. 8.Greenwood E, Cao M, Lee CM, et al. Haplotype rather than single causal variants effects contribute to regulatory gene expression associations in human myeloid cells. bioRxiv [Preprint]. 2025 Jan 30:2025.01.30.635675. doi: 10.1101/2025.01.30.635675. PMID: 39975189. 9.Rezvan A, Romain G, Fathi M, et al. Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic multidimensional single-cell profiling. Nat Cancer. 2024 Jul;5(7):1010-1023. doi: 10.1038/s43018-024-00768-3. Epub 2024 May 15. 10.Xu J, Chen C, Sussman JH, et al. A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia. Nat Cancer. 2025 Jan;6(1):102-122. doi: 10.1038/s43018-024-00863-5. Epub 2024 Nov 25. PMID: 39587259. 11.Wegmann, R., Bonilla, X., Casanova, R. et al. Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia. Nat Commun 15, 9402 (2024). doi: 10.1038/s41467-024-53535-4. 本文转自测序中国公众号 .

2025-12-15

·FierceBiotech

Kyverna gains clear view to first CAR-T approval for autoimmune disease after \'truly remarkable\' SPS readout

Strong clinical trial data set Kyverna Therapeutics\' mivocabtagene autoleucel up for an FDA filing in stiff person syndrome in the first half of 2026, potentially making it the first approved CAR-T therapy for an autoimmune disease. \n Kyverna Therapeutics looks all the more likely to win the first FDA approval for a CAR-T therapy in an autoimmune disease after a registrational trial showed “highly statistically significant” benefits for the company’s mivocabtagene autoleucel (miv-cel) on its primary endpoint and all secondary endpoints, according to the company.A single dose of miv-cel showed “truly remarkable” results in the phase 2 KYSA-8 trial in patients with stiff person syndrome (SPS) who had an inadequate response with non-approved treatment options, Amanda Piquet, M.D., director of autoimmune neurology from the University of Colorado Anshutz School of Medicine and lead investigator of the study, said during a conference call Dec. 15.SPS is a rare, progressive neurological autoimmune disease in which muscle stiffness and spasms throughout the body cause up to 80% of patients to lose mobility, meaning they need walking aid or a wheelchair. The public became more familiar with the condition following Céline Dion’s diagnosis. For this disorder, which is estimated to affect about 1 to 2 people per million, there are currently no FDA-approved therapies. Instead, off-label immunotherapies, meds to address the symptoms, psychiatric therapy and other supportive care are offered to patients.Miv-cel, formerly KYV-101, is an autologous CD19-targeted CAR-T cell therapy designed to eliminate CD19-positive B cells to reset the immune system. The one-time therapy’s CAR design includes a CD28 co-stimulatory module to enhance the therapeutic cells’ persistence and potency for a potentially more durable effect.In the registrational KYSA-8 trial, miv-cel on average reduced the time that 26 patients took to finish a 25-foot walk test by 46% at Week 16 compared with baseline. The result’s p-value was 0.0002, suggesting it’s very unlikely that the improvement happened by chance. Among them, 81% of patients achieved a clinically meaningful reduction of at least 20%.Further, the trial included secondary endpoints measuring patients’ degree of disability, muscle stiffness in various parts of the body, the triggers of muscle spasms and the combination of time and assistance used to complete the 25-foot walk test.“It was important to include all of these measures in our trial to ensure a robust evaluation of miv-cel efficacy,” Kyverna’s chief medical and development officer, Naji Gehchan, said on Monday’s call.While the detailed efficacy data from the secondary endpoints won’t be shared until a future medical conference, the p-value for every one of them was below 0.0001, which is highly statistically significant, according to Kyverna.These are “unprecedented” results that doctors have never seen with existing off-label therapies, Piquet said. Miv-cel also showed what Kyverna called a manageable safety profile. Ninety-two percent of patients developed cytokine release syndrome, but only at grade 1 or 2, and 12% experienced immune effector cell-associated neurotoxicity syndrome only at grade 1. Sixteen patients (62%) had grade 3 or 4 neutropenia, another known adverse event associated with CAR-T treatments.Based on the data, Piquet suggested that miv-cel could be beneficial for patients even beyond the eligibility criteria of the current study.“We know this disease to be progressive, so even patients that are stable right now in our clinical practice likely won\'t be in the future,” Piquet said. “Given the fact that these off-label treatments are often inadequate or the durability of response is not sustained […] these patients may be candidates for miv-cel in the future.”With these data, Kyverna plans to file for FDA approval in the first half of 2026. The drug has received regenerative medicine advanced therapy and orphan drug designations in SPS, and Kyverna has had a “really strong and consistent dialogue with the FDA,” Kyverna CEO Warner Biddle said on Monday’s call.The company plans to initially target about 2,000 to 2,500 patients treated with off-label immunotherapy, while the company put the total addressable market for miv-cel in the U.S. at about 5,500 patients, or 90% of all SPS patients diagnosed.The company continues to “assess the opportunity to accelerate the development and the filing” for miv-cel, Biddle said in response to a question about whether Kyverna will seek a Commissioner’s National Priority Voucher, a recently launched pilot program by the FDA that aims to accelerate the review of drugs that align with certain U.S. national priorities. Monday, the FDA doled out a voucher to Johnson & Johnson based on that company\'s “potentially transformative“ trial result in relapsed/refractory multiple myeloma, agency Commissioner Marty Makary, M.D., said in a statement.Analysts on Monday’s call also called the results “remarkable” or “stellar.” In a Dec. 15 note, Leerink Partners analysts called the readout a “best-case scenario” for Kyverna, as it comes ahead of the company’s guided timeline of an early 2026 report. The Bay Area biotech’s stock price jumped about 30% Monday morning as of publication time.Patients in the KYSA-8 trial will be followed for a year. So far, 16 patients have had at least 24 weeks of follow-up. All patients remained free of immunotherapies as of the last follow-up.“We believe this highlights miv-cel’s potential to provide unprecedented clinical benefit, while significantly reducing or eliminating chronic treatment burden,” the Leerink team wrote in their note. CD19 CAR-Ts have been approved for various blood cancers. Enthusiasm around them for the treatment of autoimmune disorders was sparked by early clinical evidence in lupus.While lupus has attracted a lot of interest, Kyverna picked SPS to be miv-cel’s initial indication so it can be the first CAR-T to enter the autoimmune field.SPS is “our tip of the spear that will allow us to establish a base as the first autoimmune CAR company,” Biddle, who joined Kyverna from Gilead Sciences’ cell therapy outfit Kite Pharma, said in an interview with Fierce Biotech in January.The company has also reported promising phase 2 results for miv-cel in generalized myasthenia gravis. Phase 1 lupus nephritis data are expected in 2026.

$Kyverna gains clear view to first CAR-T approval for autoimmune disease after \'truly remarkable\' SPS readout$

临床结果免疫疗法孤儿药临床2期细胞疗法

2025-12-15

·EndPoints

Kyverna to take autoimmune CAR-T to FDA after success in stiff person syndrome trial

Kyverna Therapeutics’ CAR-T therapy succeeded in a key study in stiff person syndrome, a rare autoimmune disorder that leads to painful muscle spasms and stiffness. The California biotech said Monday that it is now headed to the FDA in the first half of next year to ask for approval, which could make it the first on the market with a commercial CAR-T therapy for an autoimmune disease. Stiff person syndrome is a tiny indication, with about 6,000 patients in the US. But an approval would mark a key first step for the use of CAR-T therapies outside of cancer. Many cell therapy makers, including major pharma companies like Bristol Myers Squibb and Novartis , are likewise studying CAR-T therapies in autoimmune diseases as the industry seeks to expand the use of the one-time treatment. Stiff person syndrome “is only the beginning for Kyverna. If approved, we will have a first-mover advantage with miv-cel,” CEO Warner Biddle said on an analyst call Monday. “This advantage provides a springboard to launch into broader indications, including myasthenia gravis.” The company’s Phase 2/3 myasthenia gravis trial is expected to read out in 2027, according to a federal clinical trials database . Kyverna’s stock $KYTX jumped 53% on Monday morning. Stiff person syndrome is an autoimmune condition which was in the spotlight after the diagnosis of singer Celine Dion. It’s currently treated using a number of therapies, including drugs that address the muscle symptoms, and immunotherapies. In the single-arm, Phase 2 trial, 26 people with stiff person syndrome received a single dose of Kyverna’s cell therapy miv-cel. Treatment led to a 46% improvement in mobility at week 16, based on a timed walking test. Eight of 12 patients who needed a walking aid prior to treatment no longer needed it at week 16. The one-time therapy could also reduce the need for chronic treatments: Since receiving the CAR-T, no patients have needed other immunotherapies or rescue therapy. Sixteen of the patients experienced serious cases of neutropenia, a measure of white blood cells, according to Kyverna’s presentation, and there were mild-to-moderate cases of CAR-T-related side effects such as cytokine release syndrome, and the neurotoxicity side effect known as ICANS.

免疫疗法细胞疗法临床2期临床结果

100 项与 Cocaine and amphetamine-regulated transcript(Nankai University) 相关的药物交易

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