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The NKG2/HLA-E Axis Influence Outcomes of Haploidentical Transplantation
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/j.jtct.2025.02.008
Lamberto Torralba-Raga , Karl-Johan Malmberg
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引用次数: 0
Defining the Quality Attributes for Tumor-Infiltrating Lymphocyte Medicinal Products
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/j.jtct.2024.04.015
Justin J. Lievense , Cynthia Nijenhuis , Inge Jedema , Arendien Jonker-Hoogerkamp , Justin T. Moyers , Omid Hamid , Jos H. Beijnen , John B.A.G. Haanen , Bastiaan Nuijen
Tumor-infiltrating lymphocyte (TIL) medicinal products (MPs) show promise for treating solid tumors, especially metastatic melanoma, in the clinical trial setting. Through these studies, TIL developers have gained an immunological perspective into the mechanism of action (MoA) and infusion product characteristics that influence clinical response. However, to reach marketing authorization for any of the TIL MPs, it will be beneficial to gain a pharmaceutical (process) development perspective as well, from which control of the TIL MPs manufacturing process can be demonstrated and a suitable control strategy can be developed. To do this, a well-defined TIL MP must be established. Defining and optimizing MPs from a pharmaceutical perspective is done by identifying and improving product characteristics or quality attributes (QAs) thought to impact safety and efficacy. Through awareness of the QAs relevant to TIL MPs and considering them throughout pharmaceutical development, improvements and changes can be validated. This approach to pharmaceutical development is part of the quality-by-design workflow, of which this review tackles the first steps. Here, the QAs are structured within a quality target product profile (QTPP), and the corresponding regulatory expectations are considered, spanning quantity, identity, purity, microbiological assays, and biological activity. Based on the regulatory expectations and available literature, the (critical) QAs and points of consideration are proposed when developing TIL MPs. The active pharmaceutical ingredient of the TIL MP is defined as the CD45+CD3+ cells. By analyzing identity attributes correlated to clinical efficacy, four broadly applicable in vivo functionalities associated with TIL MPs MoA and clinical effectiveness are described: tumor recognition, cytotoxic capacity, tumor homing, and persistence. How these in vivo functionalities are quantified in potency assays and the limitations of their methods/readouts are also discussed. The QTPP is a foundation for developing a robust, substantiated control strategy for regulatory approval and increasing patient access. Harmonizing TIL MP development under a unified QTPP applicable in different settings could also facilitate comparisons and, therefore, the development of safer and more efficacious TIL MP variations.
{"title":"Defining the Quality Attributes for Tumor-Infiltrating Lymphocyte Medicinal Products","authors":"Justin J. Lievense ,&nbsp;Cynthia Nijenhuis ,&nbsp;Inge Jedema ,&nbsp;Arendien Jonker-Hoogerkamp ,&nbsp;Justin T. Moyers ,&nbsp;Omid Hamid ,&nbsp;Jos H. Beijnen ,&nbsp;John B.A.G. Haanen ,&nbsp;Bastiaan Nuijen","doi":"10.1016/j.jtct.2024.04.015","DOIUrl":"10.1016/j.jtct.2024.04.015","url":null,"abstract":"<div><div>Tumor-infiltrating lymphocyte (TIL) medicinal products (MPs) show promise for treating solid tumors, especially metastatic melanoma, in the clinical trial setting. Through these studies, TIL developers have gained an immunological perspective into the mechanism of action (MoA) and infusion product characteristics that influence clinical response. However, to reach marketing authorization for any of the TIL MPs, it will be beneficial to gain a pharmaceutical (process) development perspective as well, from which control of the TIL MPs manufacturing process can be demonstrated and a suitable control strategy can be developed. To do this, a well-defined TIL MP must be established. Defining and optimizing MPs from a pharmaceutical perspective is done by identifying and improving product characteristics or quality attributes (QAs) thought to impact safety and efficacy. Through awareness of the QAs relevant to TIL MPs and considering them throughout pharmaceutical development, improvements and changes can be validated. This approach to pharmaceutical development is part of the quality-by-design workflow, of which this review tackles the first steps. Here, the QAs are structured within a quality target product profile (QTPP), and the corresponding regulatory expectations are considered, spanning quantity, identity, purity, microbiological assays, and biological activity. Based on the regulatory expectations and available literature, the (critical) QAs and points of consideration are proposed when developing TIL MPs. The active pharmaceutical ingredient of the TIL MP is defined as the CD45+CD3+ cells. By analyzing identity attributes correlated to clinical efficacy, four broadly applicable <em>in vivo</em> functionalities associated with TIL MPs MoA and clinical effectiveness are described: tumor recognition, cytotoxic capacity, tumor homing, and persistence. How these <em>in vivo</em> functionalities are quantified in potency assays and the limitations of their methods/readouts are also discussed. The QTPP is a foundation for developing a robust, substantiated control strategy for regulatory approval and increasing patient access. Harmonizing TIL MP development under a unified QTPP applicable in different settings could also facilitate comparisons and, therefore, the development of safer and more efficacious TIL MP variations.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 3","pages":"Pages S610-S625"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143610676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reduced Chimeric Antigen Receptor T Cell Expansion Postinfusion Is Associated with Poor Survival in Patients with Large B Cell Lymphoma after Two or More Therapies 大B细胞淋巴瘤患者在两次或两次以上治疗后,输注后CAR - T扩增减少与生存率低相关。
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/j.jtct.2025.01.001
Edward Abadir , Rebecca Wayte , Wenlong Li , Sachin Gupta , Shihong Yang , Elizabeth Reaiche , Katrina Debosz , Emily Anderson , James Favaloro , Esther Aklilu , Christina Brown , Christian Bryant , Scott Dunkley , Derek McCulloch , Stephen Larsen , John E.J. Rasko , Vinay Vanguru , P. Joy Ho
CD19-directed chimeric antigen receptor T cell (CAR-T) therapy is now standard of care for relapsed/refractory large B cell non-Hodgkin lymphoma. Despite good overall response rates, many patients still experience disease progression and therefore it is important to predict those at risk of relapse following CAR-T therapy. We performed a prospective study using a flow cytometry assay at a single treatment center to assess early CAR T cell expansion in vivo 6 to 9 days after CAR T cell infusion. Early CAR T cell expansion was used in conjunction with additional clinical risk factors to identify those at greater risk of relapse or treatment failure. Forty-four patients treated with commercial CD19-directed CAR-T therapy were included in the study, with a median follow-up of 306 days. CAR T cell expansion of >30 cells/μL was associated with a lower risk of disease progression or death (hazard ratio, 0.34; P = .048), but did not correlate with the risk of death alone. Patients who had poor early CAR T cell expansion (<30 cells/μL) in addition to high lactate dehydrogenase (LDH) had significantly lower median progression-free survival and overall survival. High LDH level alone was not a statistically significant risk factor for death or disease progression, and thus the interaction between CAR T cell expansion and this clinical risk factor may be important in predicting response. The mean CAR T cell count was higher in patients with grade 2 to 4 cytokine release syndrome (CRS) compared to those with grade 0 to 1 CRS (54.9 cells/μL versus 25.5 cells/μL; P = .01). The methodology of this assay is easily reproducible outside of a clinical trial, allowing for real-life implementation in clinical settings. This study suggests that early assessment of CAR T cell expansion can assist in identifying patients with poor overall survival who may benefit from early intervention or more intensive monitoring.
CD19靶向嵌合抗原受体(CAR) t细胞疗法现在是复发/难治性大b细胞非霍奇金淋巴瘤的标准治疗方法。尽管总体反应率良好,但许多患者仍经历疾病进展,因此预测CAR - t细胞治疗后复发风险很重要。我们在单个治疗中心使用流式细胞术进行了一项前瞻性研究,以评估CAR- t细胞输注后6 - 9天体内早期CAR- t细胞的扩增情况。早期CAR - t细胞扩增与其他临床风险因素一起用于识别复发或治疗失败风险较高的患者。44名接受商业化CD19靶向CAR - t细胞治疗的患者被纳入研究,中位随访时间为306天。CAR - t细胞扩增量为bbb30个细胞/μl与疾病进展或死亡风险降低相关(HR 0.34, p=0.048),但与死亡风险无关。早期CAR - t细胞扩增不良的患者(
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引用次数: 0
Tumor-Infiltrating Lymphocyte Therapy for Melanoma and Other Solid Tumors: Looking Back, Yet Moving Forward
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/j.jtct.2024.11.017
Alexander N. Shoushtari , Daniel J. Powell
Lifileucel, the first solid tumor adoptive tumor infiltrating lymphocyte (TIL) therapy product to receive regulatory approval in advanced melanoma, represents a critical achievement in the pursuit of improving outcomes using cellular therapies in patients with solid tumors. This review traces the development of adoptive TIL therapy from the initial human studies in melanoma, through recent advances in studies of other solid tumors, and previews ongoing and future areas for preclinical and clinical advances to improve upon this novel therapeutic strategy.
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引用次数: 0
Officers and Directors of ASTCT
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/S2666-6367(25)01017-6
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引用次数: 0
Early Engraftment and Immune Kinetics Following Allogeneic Transplant Using a Novel Reduced-Toxicity Transplant Strategy in Children/Adolescents with High-Risk Transfusion-Dependent Thalassemia: Early Results of the ThalFAbS Trial 使用一种新型的低毒性移植策略对患有高危输血依赖性地中海贫血的儿童/青少年进行异体移植后的早期移植和免疫动力学:ThalFAbS试验的早期结果
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/j.jtct.2024.12.016
Enass H Raffa , Taylor M Harris , Chane Choed-Amphai , Melanie Kirby-Allen , Isaac Odame , Muhammad Ali , Joerg Krueger , Karin G Hermans , Soumitra Tole , Jennifer Seelisch , Robert J Klaassen , Lesleigh Abbott , Yogi Raj Chopra , Donna A Wall , Kuang-Yueh Chiang
Allogeneic hematopoietic stem cell transplantation is challenging for patients with transfusion-dependent thalassemia who have experienced iron overload and received chronic transfusion support. A transplantation strategy including a reduced-intensity preparative regimen and tailored immunosuppression to support donor engraftment and prevent graft-versus-host disease (GVHD) was developed for this population. The combination of a pretransplantation immunosuppression phase with reduced dosing of fludarabine/prednisone, a treosulfan-based preparative regimen with reduced cyclophosphamide dosing, and introduction of a calcineurin/methotrexate-free GVHD prophylaxis/engraftment supporting regimen with abatacept/sirolimus/antithymocyte globulin was tested. In the ThalFAbS trial, a prospective pilot trial (ClinicalTrials.gov NCT05426252) of a transplantation strategy designed for higher-risk patients with transfusion-dependent thalassemia, 12 pediatric patients (4 with alpha thalassemia, 8 with beta thalassemia) were treated with this strategy. Descriptive statistics were used to characterize transplantation outcomes and immune recovery. With a median follow-up of 12 months (range, 4 to 26 months) post-transplantation, all 12 patients had prompt and durable trilineage donor engraftment with low transplantation-related morbidity and acute GVHD and are alive without transfusion support at the time of this report. GVHD was limited to 1 patient with skin-only grade II acute GVHD and 3 patients with limited oral chronic GVHD. Early hematologic and immunologic recovery was achieved, with low rates of transfusion support and infection. Neutrophil recovery occurred at a median of 18 days (range, 15 to 24 days), and platelet recovery occurred at a median of 18 days (range, 12 to 36 days). No patients experienced veno-occlusive disease, transplantation-associated thrombotic microangiopathy, or sepsis. This platform was sufficient to support haploidentical donor transplantation in 2 patients. The ThalFAbS approach is tailored to meet the unique needs of transfusion-dependent thalassemia patients. Delivery of this novel regimen is feasible, and it shows excellent early engraftment and transplantation outcomes. Further follow-up of this cohort and expansion of patient numbers is needed before the findings can be generalized, but early experience is promising.
背景:输血依赖性地中海贫血患者的同种异体移植是具有挑战性的,一旦有铁超载和慢性输血支持。目的:为这一人群开发了一种移植策略,即降低准备方案的强度和量身定制的免疫抑制,以支持供体移植和预防GVHD。移植前免疫抑制期减少氟达拉滨/泼尼松的剂量,以曲硫胺为基础的制备方案减少环磷酰胺的剂量,引入钙调磷酸酶/无甲氨蝶呤的GVHD预防/植入支持方案与阿巴接受普/西罗莫司/ATG的组合进行了测试。研究设计:ThalFAbS试验是一项前瞻性试点试验(NCT05426252),为12名儿科患者(4名α型地中海贫血,8名β型地中海贫血)设计了一种移植策略,用于治疗输血依赖性地中海贫血的高风险患者。描述性统计用于描述移植结果和免疫恢复。结果:移植后中位随访12个月(范围4-26个月),首批12例患者均及时且持久地进行了三岁供体移植,移植相关发病率和急性GVHD较低,并且在没有输血支持的情况下存活。GVHD仅限于1例2级皮肤急性GVHD患者和3例有限口腔慢性GVHD患者。在低输血支持和低感染率的情况下实现了早期血液学和免疫恢复。中性粒细胞恢复的中位时间为18天(15-24天),血小板恢复的中位时间为18天(12-36天)。无VOD、TA-TMA、败血症。该平台足以支持2例患者的单倍体供体移植。结论:ThalFAbS方法是为满足输血依赖型地中海贫血患者的独特需求而量身定制的。这种新方案的交付是可行的,并显示出良好的早期植入和移植结果。在推广之前,需要对该队列进行进一步随访并扩大患者数量,但早期经验是有希望的。
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引用次数: 0
Outcomes of Standard-Risk Multiple Myeloma Patients Who Undergo Upfront Autologous Hematopoietic Stem Cell Transplantation 标准风险多发性骨髓瘤患者接受前期自体造血干细胞移植的结果
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/j.jtct.2024.12.023
Oren Pasvolsky , Curtis Marcoux , Zhongya Wang , Denái R. Milton , Babar Pal , Mark R. Tanner , Qaiser Bashir , Samer Srour , Neeraj Saini , Paul Lin , Jeremy Ramdial , Yago Nieto , Guilin Tang , Naureen Syed , Yosra Aljawai , Hans C. Lee , Krina K. Patel , Melody R. Becnel , Christine Ye , Partow Kebriaei , Muzaffar H. Qazilbash
Patients with multiple myeloma (MM) without high-risk cytogenetic abnormalities are classified as having standard-risk MM (SRMM), and data focusing on their outcomes after autologous hematopoietic stem cell transplantation (autoHCT) are limited. We sought to evaluate survival outcomes for patients with SRMM receiving autoHCT, and to elucidate factors that impact these outcomes. This was a single-center retrospective analysis that included consecutive MM patients who received upfront autoHCT between 2013 and 2021, had available cytogenetic information and had no high-risk chromosomal abnormalities on fluorescence in situ hybridization, defined as t(4;14), t(14;16), del(17p) or 1q21 gain or amplification. A total of 1000 SRMM patients were included, with a median age of 61 years (range 25 to 83), and 61% were male (n = 612). The most common induction regimens were bortezomib/lenalidomide/dexamethasone (VRD; n = 398, 40%) and carfilzomib/lenalidomide/dexamethasone (KRD; n = 212, 21%), and the majority (87%) received single-agent melphalan as conditioning. After induction and before autoHCT, 16% and 57% achieved ≥complete response (CR) and ≥very good partial response (VGPR), respectively. At day 100 post autoHCT, 37% and 77% achieved ≥CR and ≥VGPR, respectively. Sixty-two percent and 89% of patients achieved ≥ CR and ≥VGPR as best response post-transplant. A minimal residual disease (MRD) negative response pre- and post-transplantation was achieved in 43% (401/936) and 64% (199/311) of patients, respectively. After a median follow-up of 42.1 months, the median progression-free survival (PFS) for the entire cohort was 68.3 months (95% CI 60.1 to 72.1), and the median overall survival (OS) was not reached (95% CI 102.3-not reached). The 5-year PFS and OS rates were 55% and 83%, respectively. In multivariable analysis, achieving MRD-negative CR prior to autoHCT (HR 0.65 [95% CI 0.44 to 0.97], P = .033) or as best response (0.52 [0.34 to 0.78], P = .002), and use of post-transplant maintenance (0.69 [0.52 to 0.93], P = .013) and lenalidomide-based combination maintenance (0.68 [0.48 to 0.96], P = .030) were associated with improved PFS, whereas use of an induction regimen other than KRD was associated with worse PFS (1.50 [1.04 to 2.17], P = .031). For OS, post-transplant maintenance (0.48 [0.32 to 0.70], P < .001) was associated with better survival in multivariable analysis, whereas R-ISS stage III, compared with stage I, (2.34 [1.01 to 5.43], P = .047) was associated with worse OS. Patients with SRMM who received upfront autoHCT had a median PFS of >5.5 years, and median OS was not reached. These results highlight the favorable outcomes with upfront autoHCT for patients with SRMM, serving as a benchmark for future therapeutic approaches in this subgroup of MM patients.
背景:没有高危细胞遗传学异常的多发性骨髓瘤患者被归类为标准风险MM (SRMM),关注其自体干细胞移植(autoHCT)后结果的数据有限。目的:评估接受自体hct治疗的SRMM患者的生存结果,并阐明影响这些结果的因素。研究设计:单中心回顾性分析,纳入2013-2021年间接受前期autoHCT的连续MM患者,具有可用的细胞遗传学信息,荧光原位杂交(FISH)无高危染色体异常,定义为t(4;14), t(14;16), del(17p)或1q21获得或扩增。结果:共纳入1000例SRMM患者,中位年龄61岁(25-83岁),61%为男性(n=612)。最常见的诱导方案是硼替佐米/来那度胺/地塞米松(VRD;n=398, 40%)和卡非佐米/来那度胺/地塞米松(KRD;N =212, 21%),大多数(87%)接受单药美法兰作为条件反射。诱导后和autoHCT前,分别有16%和57%的患者达到≥完全缓解(CR)和≥极好部分缓解(VGPR)。在autoHCT后第100天,分别有37%和77%的患者达到≥CR和≥VGPR。62%和89%的患者在移植后达到了≥CR和≥VGPR的最佳反应。43%(401/936)和64%(199/311)的患者在移植前和移植后分别出现可测量的残留病(MRD)阴性反应。中位随访42.1个月后,整个队列的中位PFS为68.3个月(95% CI 60.1-72.1),中位OS未达到(95% CI 102.3-未达到)。5年PFS和OS率分别为55%和83%。在多变量分析中,在autoHCT之前达到mrd阴性CR (HR 0.65 [95% CI 0.44 - 0.97], p=0.033)或最佳反应(0.52 [0.34 - 0.78],p=0.002),以及移植后维持(0.69 [0.52 - 0.93],p=0.013)和来那度胺联合维持(0.68 [0.48 - 0.96],p=0.030)与PFS改善相关,而使用非KRD的诱导方案与PFS恶化相关(1.50 [1.04 - 2.17],p=0.031)。对于OS,移植后维持(0.48 [0.32 - 0.70],p)结论:接受前期autoHCT的SRMM患者的中位PFS为bb0 - 5.5年,中位OS未达到。这些结果强调了SRMM患者采用早期自体hct治疗的良好结果,可作为SRMM患者亚组未来治疗方法的基准。
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引用次数: 0
Masthead (Purpose and Scope)
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/S2666-6367(25)01026-7
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引用次数: 0
CAR-T — The Slow and the Spurious
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/j.jtct.2025.02.007
Vinodh Pillai
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引用次数: 0
Engraft: A Collaborative Learning Health Network for Enhanced Transplant and Cellular Therapy Outcomes 移植:促进移植和细胞治疗结果的协作学习健康网络。
IF 3.6 3区 医学 Q2 HEMATOLOGY Pub Date : 2025-03-01 DOI: 10.1016/j.jtct.2024.12.017
Christopher E. Dandoy , Jeffery J. Auletta , Priscila Badia , Alan Bidgoli , Nancy M. Daraiseh , Anna M. DeSalvo , Javier Diaz , Stella M. Davies , Kathleen Demmel , Eleanor Cook , John A. Craddock , John Huber , Megan Sampson , Taylor J. Fitch , Karis French , Sonata Jodele , Samantha M. Jaglowski , Malika A. Kapadia , Nandita Khera , Georgia R. Kent , David Hartley
The Engraft Learning Health Network (LHN) aims to improve outcomes for patients undergoing transplant and cellular therapy (TCT) through a collaborative, data-driven approach. Engraft brings together diverse stakeholders, including clinicians, patients, caregivers, and institutions, to standardize best practices and accelerate the dissemination of innovations in TCT care. By establishing a multicenter, real-world clinical registry focused on rapid-cycle quality improvement (QI) and implementation research, Engraft seeks to reduce variability in clinical practice to improve TCT outcomes across centers. Initial efforts have centered on developing QI toolkits, sharing de-identified patient data, and building consensus around best practices to reduce non-relapse mortality and improve survivorship. A distinctive feature of Engraft is its commitment to engaging patients and caregivers as equal partners in the network's direction. This manuscript outlines the network's design, early successes, and future goals.
移植物学习健康网络(LHN)旨在通过协作、数据驱动的方法改善接受移植和细胞治疗(TCT)患者的预后。Engraft将包括临床医生、患者、护理人员和机构在内的不同利益攸关方聚集在一起,使最佳做法标准化,并加速TCT护理创新的传播。通过建立一个多中心、真实世界的临床注册中心,专注于快速循环质量改进(QI)和实施研究,Engraft寻求减少临床实践中的可变性,以改善各中心的TCT结果。最初的努力集中在开发QI工具包,共享去识别的患者数据,并围绕降低非复发死亡率和提高生存率的最佳实践建立共识。Engraft的一个显著特点是它致力于让患者和护理人员在网络的发展方向上成为平等的合作伙伴。这份手稿概述了网络的设计、早期的成功和未来的目标。
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引用次数: 0
期刊
Transplantation and Cellular Therapy
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