Clinical short-term and long-term efficacy of targeted cd19-cart in the treatment of relapsed and refractory childhood B-line acute lymphoblastic leukemia

开始日期2017-03-20

申办/合作机构-

100 项与 CD19-CART (Shanghai Children's Medical Center) 相关的临床结果

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100 项与 CD19-CART (Shanghai Children's Medical Center) 相关的转化医学

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100 项与 CD19-CART (Shanghai Children's Medical Center) 相关的专利（医药）

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项与 CD19-CART (Shanghai Children's Medical Center) 相关的文献（医药）

2024-11-15·CLINICAL CANCER RESEARCH

Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma

Article

作者: Leithner, Doris ; Shah, Gunjan ; Lin, Richard J. ; Devlin, Sean ; Palomba, Maria L. ; Salles, Gilles ; Fregonese, Beatrice ; Imber, Brandon S. ; Bedmutha, Akshay ; Schöder, Heiko ; Dahi, Parastoo B. ; Shouval, Roni ; Perales, Miguel-Angel ; Parascondola, Allison ; Wills, Beatriz ; Silverman, Emily A. ; Saldia, Amethyst ; Hajj, Carla ; Boardman, Alexander P. ; Hubbeling, Harper ; Yahalom, Joachim ; Alarcon Tomas, Ana ; Ghosh, Arnab ; Landego, Ivan ; Scordo, Michael ; Giralt, Sergio ; Flynn, Jessica ; Park, Jae

Abstract:

Purpose::

Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell (CAR T) therapy. Although bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data have evaluated the impact of BT on CAR T outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic.

Experimental Design::

Patients with large B-cell lymphoma treated with CD19-CAR T from 2016 to 2022 were included in the study. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into “High” and “Low” disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression-free survival (PFS).

Results::

Of 191 patients treated with CAR T, 144 (75%) received BT. In the BT cohort, 56% had a reduction in MTV post-BT. On multivariate analysis, the MTV trajectory across the bridging period remained significantly associated with PFS (P < 0.001); however, notably, patients with improved MTV (High->Low) had equivalent PFS compared with those with initially and persistently low MTV (Low->Low; HR for High->Low MTV: 2.74; 95% confidence interval, 0.82–9.18). There was a reduction in any grade immune effector cell–associated neurotoxicity syndrome in the High->Low MTV cohort as compared with the High->High MTV cohort (13% vs. 41%; P = 0.05).

Conclusions::

This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real-world large B-cell lymphoma cohort. We demonstrate that effective BT can enable initially high–disease burden patients to achieve post–CAR T outcomes comparable with low–disease burden patients.

2024-11-01·MOLECULAR THERAPY

ARI0003: Co-transduced CD19/BCMA dual-targeting CAR-T cells for the treatment of non-Hodgkin lymphoma

Article

作者: Antoñana-Vildosola, Asier ; Guedan, Sonia ; Fillat, Cristina ; Juan, Manel ; Español-Rego, Marta ; Castellsagué, Joan ; Delgado, Julio ; Pascal, Mariona ; Alserawan, Leticia ; Rodríguez-Garcia, Alba ; Anguela, Xavier M ; Pérez-Galán, Patricia ; Bachiller, Mireia ; Ferruz, Noelia ; Otero-Mateo, Marc ; Olesti, Eulàlia ; Calvo, Gonzalo ; Barceló-Genestar, Nina ; Dobaño-López, Cèlia ; Anguela, Xavier M. ; Rodriguez-Garcia, Alba ; Giménez-Alejandre, Marta ; Urbano-Ispizua, Álvaro ; Colell, Salut ; Martín-Antonio, Beatriz

CD19 CAR-T therapy has achieved remarkable responses in relapsed/refractory non-Hodgkin lymphoma (NHL). However, challenges persist, with refractory responses or relapses after CAR-T administration linked to CD19 loss or downregulation. Given the co-expression of CD19 and BCMA in NHL, we hypothesized that dual targeting could enhance long-term efficacy. We optimized different dual-targeting approaches, including co-transduction of two lentiviral vectors, bicistronic, tandem, and loop and pool strategies, based on our academic anti-CD19 (ARI0001) and anti-BCMA (ARI0002h) CAR-T cells. Comparison with anti-CD19/CD20 or anti-CD19/CD22 dual targeting was also performed. We demonstrate that anti-CD19/BCMA CAR-T cells can be effectively generated through the co-transduction of two lentiviral vectors after optimization to minimize competition for cellular resources. Co-transduced T cells, called ARI0003, effectively targeted NHL tumor cells with high avidity, outperforming anti-CD19 CAR-T cells and other dual-targeting approaches both in vitro and in vivo, particularly in low CD19 antigen density models. ARI0003 maintained effectiveness post-CD19 CAR-T treatment in xenograft models and in spheroids from relapsed CART-treated patients. ARI0003 CAR-T cells were effectively manufactured under Good Manufacturing Practice conditions, with a reduced risk of genotoxicity compared to other dual-targeting approaches. A first-in-human phase 1 clinical trial (CARTD-BG-01; this study was registered at ClinicalTrials.gov [NCT06097455]) has been initiated to evaluate the safety and efficacy of ARI0003 in NHL.

2024-08-01·HemaSphere

PD‐L1⁺ macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B‐cell lymphoma microenvironment impact CD19 CAR‐T cell immunotherapy efficacy

Article

作者: Hirayama, Alexandre V. ; Gauthier, Jordan ; Naresh, Kikkeri N. ; Turtle, Cameron J. ; Shaw, Akira N. ; Fiorenza, Salvatore ; Maloney, David G. ; Wright, Jocelyn H. ; Yeung, Cecilia C. S. ; Smythe, Kimberly S.

Abstract:

CD19‐targeted chimeric antigen receptor T‐cell (CAR‐T) immunotherapy has transformed the management of relapsed/refractory large B‐cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR‐T therapy outcomes. Using NanoString nCounter transcriptome profiling (n = 24) and multiplex immunohistochemistry (mIHC, n = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR‐T therapy. Patients who achieved complete response (CR) after CAR‐T therapy demonstrated higher expression of genes associated with T‐cell trafficking and function, whereas those who did not achieve CR had higher expression of genes associated with macrophages and T‐cell dysfunction. Distinct patterns of immune infiltration and fibrosis in the TME were associated with CAR‐T therapy outcomes, and these findings were corroborated using artificial intelligence‐assisted image analyses. Patients who achieved CR had a lower proportion of the biopsy occupied by an interspersed immune infiltrate and a higher proportion of hypocellular/fibrotic regions. Furthermore, mIHC revealed lower density of CD4+ T cells and higher densities of both macrophages and tumor cells expressing PD‐L1 in non‐CR patients. Spatial analysis revealed that PD‐1+ T cells were in close proximity to PD‐L1+ macrophages or PD‐L1+ tumor cells in patients who did not compared to those who did achieve CR after CAR‐T therapy. These findings suggest that morphologic patterns in the TME and engagement of the PD‐1/PD‐L1 axis in pretreatment biopsies may impact CD19 CAR‐T immunotherapy response in patients with LBCL.

项与 CD19-CART (Shanghai Children's Medical Center) 相关的新闻（医药）

2024-11-30

·学术经纬

《自然-医学》：CAR-T疗法研究获得全新进展，可有效治疗T细胞急淋白血病

撰文 | 周叶斌 T细胞急性淋巴细胞白血病（T-ALL）是儿童中最常见的癌症——急性淋巴细胞白血病（ALL）的一个亚型。T-ALL起源于T细胞前体的致癌转化，占儿童ALL病例的约10%，以及青少年和年轻成人病例的25-30%。与B细胞ALL相比，T-ALL具有更高比例的预后不良特征，并且在大多数治疗方案下效果较差。复发或难治性B细胞ALL患者的治疗因靶向B细胞标志物CD19的嵌合抗原受体（CAR）的开发而出现了革命性变化，这种疗法将T淋巴细胞转变为强大的抗白血病武器，也就是CAR T细胞，已经成为B-ALL的有效治疗方案。然而，由于T-ALL通常缺乏B-ALL里CD19或CD22这些标志性抗原的表达，针对T-ALL的细胞治疗发展相对滞后。 CD7是一种的I型跨膜糖蛋白，在几乎所有T-ALL病例中均有高度表达。然而，CD7也在正常T淋巴细胞中表达，包括CAR T细胞。因此，抗CD7 CAR的表达会触发自身细胞毒性（即自相残杀），这生产可靠CAR T细胞的关键障碍。为解决这一问题，一个新加坡和意大利科学家组成的联合研究团队开发了一种抗CD7蛋白表达阻断剂（PEBL），它允许合成CD7，但将其保留在细胞内，防止其在细胞膜上表达，从而避免自相残杀。抗CD7 PEBL消除了CD7的表面表达，但对T细胞功能没有明显影响。近期，该研究团队在 Nature Medicine 上发表了题为 Fratricide-resistant CD7-CAR T cells in T-ALL 的论文，报告了17例接受自体抗CD7 PEBL-CAR T细胞治疗的T-ALL患者的结果。研究人员将抗CD7 PEBL-CAR T细胞的特性与为20例B细胞ALL患者制造的抗CD19 CAR T细胞进行了比较，发现这种CAR T治疗在T-ALL患者中安全性、有效性与B-ALL的CAR T治疗相当，显示了未来治疗复发/耐药型T-ALL的希望。从2019年4月24日至2023年10月6日，研究人员筛选了20例复发或难治性T-ALL患者以评估其是否适合接受抗CD7 PEBL-CAR T细胞治疗。其中两名患者（18岁和7岁）通过化疗实现了微小残留病（MRD）阴性的完全缓解（CR），随后接受了造血干细胞移植（HSCT）；另一名患者（16岁）在接受CAR T细胞输注前因病情进展死亡。这篇论文报告了其余接受抗CD7 PEBL-CAR T细胞治疗的17例患者的病例。研究人员通过一个双顺反子伽玛逆转录病毒载体同时表达抗CD7 PEBL和抗CD7 4-1BB–CD3ζ CAR基因，产生的CAR T细胞比例中位数为96.7%（89.1%-99.1%）。该比例显著高于使用类似载体为B细胞ALL患者制造的20个抗CD19 CAR T细胞产品。两组患者的T细胞扩增相似，表明非转导的CD7+ T细胞的清除与CAR驱动的T细胞增殖共同促进了抗CD7 PEBL-CAR T细胞的富集。所有17个起始细胞产品中均含有白血病细胞（0.01%-60.3%；中位数1.35%），但在生产好的CAR T细胞成品里均未检测到可存活的白血病细胞。附图. CAR T细胞的特征分析输注CAR T细胞后，所有17名患者的外周血中均能检测到输注的细胞。输注后1个月，CD8+ CAR T细胞通常占主导地位。其中一名患者的CD4和CD8表达在多个时间点被检测，持续时间最长达220天，但CD8表达始终占主导地位。该病例系列的首位患者中，CAR T细胞的长期持续性评估最长达输注后48个月（该患者未接受HSCT巩固）。流式细胞术显示CAR T细胞可持续检测至18个月，但在24个月和48个月的两次外周血样本中未再检测到。ddPCR的结果与流式细胞术一致，但在24个月时仍可检测到信号，48个月时消失。总体而言，该患者中CAR T细胞的长期持续性与B细胞ALL组中的抗CD19 CAR T细胞相当。 17名患者均未出现3级或更高级的细胞因子释放综合征（CRS）；10名患者发生了1级CRS，3名患者发生了2级CRS。CRS的中位发生时间为5天（范围3-8天），中位持续时间为2天（范围1-7天）。仅两名患者出现了1级的免疫效应细胞相关神经毒性综合征（ICANS）。所有患者在输注后30天内均出现了2级或更高级的免疫效应细胞相关血液毒性（ICAHT），但无一需要转入重症监护。总体而言，CD7 PEBL-CAR T细胞的治疗相关毒性与CD19 CAR T类似。输注前16名患者的骨髓中检测到白血病细胞（中位数14.1%；范围0.01%-77.9%），外周血中也有检测（中位数5.0%；范围0.03%-84.1%）。另1名患者在桥接化疗后为MRD阴性，但PET-CT显示纵隔仍有残余病变。在输注CAR T后的一个月内，16名患者在骨髓和外周血中均达到MRD阴性（CR），且影像学检查显示缓解。与CD19 CAR T治疗相比，虽然该研究中T-ALL患者们病情更严重，但CD7 PEBL-CAR T获得的MRD响应率类似。附图. CD7 PEBL-CAR T细胞治疗的效果截至2024年3月15日，CAR T细胞输注后3-55个月（中位数15个月），11名患者仍存活且无白血病。与未接受CAR T细胞治疗的复发或难治性T-ALL患者的历史队列相比，这些患者的治疗结果显著改善。对于针对T-ALL的CAR T治疗来说，一种担忧是如果抗CD7 PEBL-CAR T细胞能够杀伤T-ALL肿瘤细胞，它们可能也会抑制淋巴细胞清除后正常T和自然杀伤（NK）细胞的重建（两者均表达CD7）。但在接受抗CD7 PEBL-CAR T细胞治疗的患者中，T细胞和NK细胞均可恢复，不过恢复率通常低于接受抗CD19 CAR T细胞的患者。值得注意的是，恢复的T细胞和NK细胞缺乏CD7表达，因此能够逃避免疫攻击。再生的T细胞呈多克隆性。输注后1个月，非CAR T细胞表现为记忆表型，在所有样本中均可检测到TSCM、TCM和TEM细胞。CD4+和CD8+非CAR T细胞的比例变化较大，类似于B细胞ALL患者。上述结果表明，自体抗CD7 PEBL-CAR T细胞具有强大的抗白血病活性，是治疗T-ALL的潜在有效选择。这也意味着抗CD7 PEBL-CAR T细胞能够克服限制当前复发或难治性T-ALL治疗的耐药机制，为患者带来希望。撰文责编制作排版 | Sheila 校对 | uu 延伸阅读突破：CAR T治疗在恶性脑瘤中展现希望！首次公布数据！碱基编辑通用型CAR-T治疗儿童急淋白血病二代CAR-T细胞治疗复发难治的儿童急淋白血病竺晓凡/张英驰团队揭示儿童T-ALL癌细胞克隆演化模式及耐药新机制 *本文由深圳市拾玉儿童公益基金会“儿童肿瘤前沿”团队编译或约稿，文中图表均源引自文献原文。本文著作权归文章作者所有，欢迎个人转发分享，未经允许禁止转载，作者拥有所有法定权利，违者必究。如需转载，请留言或联系shiyu@curekids.cn。本文旨在分享儿童肿瘤科研前沿成果，不是治疗方案推荐。如需获得疾病治疗方案指导，请前往正规医院就诊。 ▼滑动查看更多▼ 原文摘要（Abstract） T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7- T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL. DOI: 10.1038/s41591-024-03228-8 👇点击此处，直达原文

细胞疗法免疫疗法临床结果

2024-11-28

·药研网

华东医药两款创新药同时获批上市，另一款CD19 CAR-T产品上市申请获受理

华东医药在创新药领域又获得重要进展。11月27日，公司一天发布了三款创新产品的研发进展。其中，两款创新药获批上市，一款创新产品NDA受理。华东医药宣布，其全球首创药物索米妥昔单抗注射液（爱拉赫®/ELAHERE®）获国家药品监督管理局（NMPA）批准，用于既往接受过1—3线系统性治疗的叶酸受体α阳性的铂类耐药卵巢癌（PROC）适应症。索米妥昔单抗注射液在中国、美国和欧盟均为首个也是目前唯一一个批准用于治疗PROC的靶向FRα的ADC药物，开创了卵巢癌治疗新途径，正式标志着PROC治疗进入了ADC时代。同日，华东医药注射用利纳西普（Rilonacept for Injection，商品名：炎朵®/ARCALYST®）的上市许可申请获得NMPA批准，用于治疗成人和12岁及以上青少年冷吡啉相关周期性综合征（CAPS），包括家族性寒冷性自身炎症综合征（FCAS）和Muckle-Wells综合征（MWS）。此外，华东医药独家商业化的靶向CD19的自体CAR-T候选产品IM19嵌合抗原受体T细胞注射液（简称“IM19”）的药品注册上市许可申请也于同日获NMPA受理。华东医药表示，将加强研发创新力度，不断丰富差异化、引领性的创新医药产品管线，积极拓展全球前沿创新药物布局，为患者提供更多具有国际领先水平的创新药物。此次全球首个卵巢癌ADC及自免罕见病创新药炎朵®获批上市，为公司的发展再添新动力。 End 声明：本公众号所有发文章(包括原创及转载文章)系出于传递更多信息之目的，且注明来源和作者。本公众号欢迎分享朋友圈或大群，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/商务/投稿 | 联系微信15618157102（sum_Gmi）商务合作稿件征集点击了解详情往期回顾 1 10月 | 20家生物医药裁员汇总 2 国产首款四价HPV疫苗拟纳入优先审评 3 3. 7亿美元!今年规模最大的生物医药融资诞生

上市批准抗体药物偶联物免疫疗法细胞疗法疫苗

2024-11-27

·ioncology

CTI 2024丨全球前沿聚焦：Marion Subklewe教授揭示AdCAR-T细胞如何双重提升AML治疗的安全性与精准度

点击蓝字关注我们 2024年11月14日至17日，国际细胞与免疫治疗（CTI）大会在中国杭州盛大举行，汇聚了全球细胞治疗和免疫治疗领域的顶尖专家、学者和行业领袖。此次大会不仅是一个学术交流的国际平台，更是一个展示最新科研成果、推动领域发展的重要窗口。会议期间，《肿瘤瞭望·血液时讯》特别邀请到德国慕尼黑大学附属医院（LMU）Marion Subklewe教授，与我们分享AdCAR-T细胞技术的原理、优势以及AML治疗未来优化方向，现整理成文，以飨读者。 Q1 Adapter CAR-T（AdCAR-T）技术在急性髓系白血病（AML）治疗中的主要优势是什么？它如何克服传统CAR-T疗法的限制？ Marion Subklewe教授：迄今为止，在急性髓系白血病（AML）治疗领域，我们在进行CAR-T细胞疗法的研究过程中，观察到的一个显著现象是，严重细胞因子释放综合征（CRS）的发生率居高不下。为应对这一挑战，我们引入了Adapter CAR-T（简称AdCAR-T）细胞技术，旨在提升CAR-T细胞治疗的安全性。 AdCAR-T细胞技术所依赖的适配分子，体积微小，其分子量精确控制在约52千道尔顿。AdCAR-T通过持续输注的方式给药，其血浆半衰期约为30分钟，这一特性确保了药物在体内的有效浓度维持及适时清除。尤为重要的是，在遭遇更高级别的毒性反应时，我们能够迅速通过停止输注适配分子来干预，这一操作模式与某些生物特异性药物的给药策略相类似。此策略不仅能够有效遏制毒性反应的进一步升级，而且有望实现副作用的中止与逆转，从而显著降低患者承受的风险。显然，这是AdCAR-T细胞技术相较于传统CAR-T疗法的一个显著且独特的优势，为急性髓系白血病患者提供了新的治疗希望与安全保障。此外，若留意临床试验的进展，便会发现目前急性髓系白血病领域的多数靶抗原聚焦于CD33、CD123及CLL-1。正因如此，近90%的临床试验均围绕这些髓系抗原展开探索。这些抗原在治疗过程中会对健康造血系统产生预期的靶向毒性，故常被视作移植前的过渡性治疗手段。相比之下，CD7作为一种靶抗原显得尤为独特，它并不在正常造血系统中表达，因此具有更高的特异性。值得注意的是，CD7在约30%的AML患者中呈阳性表达，并在《新英格兰医学杂志》上发表的相关研究中展示了令人瞩目的成果。在该研究中，患者接受了供体来源的CD7 CAR-T细胞治疗，并随后接受了异基因干细胞移植。这些患者在接受清淋治疗后，并未接受预处理或移植物抗宿主病的预防措施，这一治疗方法似乎极具潜力。然而，我们也观察到CD7抗原丢失导致疾病复发的情况。因此，我认为我们可能需要采取多靶点策略，同时针对多个抗原进行治疗，以提高疗效。否则，我们将持续面临抗原逃逸这一难题，从而影响患者的治疗效果和预后。（上下滑动查看英文原文） What are the main advantages of Adapter CAR-T (AdCAR-T) technology in the treatment of acute myeloid leukemia (AML)? How does it overcome the limitations of traditional CAR-T therapy? So what we have observed so far in CAR-T cell trials, in the context of AML, is a high incidence of severe cytokine release syndrome. Our approach using Adapter CAR-T (AdCAR-T) cells will increase the safety of CAR-T cells. These adapter molecules are small. They have a molecular weight of about 52 kilo Daltons. They are given as a continuous infusion, and their half-life is about 30 minutes.If you encounter higher-grade toxicity, you can stop the infusion of the adapter molecule, which is given as a continuous infusion similar to some of the bio-specifics, and thereby hopefully revert and stop the side effects.This is clearly one of the advantages of Adapter CAR-T (AdCAR-T) cells. Currently, if you look at clinical government trials, most of the target antigens in the context of AML are CD33, CD123, and CLL-1. So, almost 90% of the clinical trials are following these myeloid lineage antigens. These have the expected on-target toxicity on the healthy hematopoietic system and are therefore mainly done as a bridge to transplant strategy. In contrast, CD7 is a more unique target antigen that is not expressed within the healthy hematopoietic system and is therefore more specific. It is expressed in about 30% of AML patients and has been presented and published in interesting data in the New England Journal of Medicine, where patients were treated with donor-derived CD7 CAR-T cells, followed by allogeneic stem cell transplantation. These patients accept lymphoid depletion did not really need conditioning or graft-versus-host prophylaxis. This seems to be a very interesting approach. However, what has also been seen is CD7 antigen loss and relapse. So, I think we probably need to target multiple antigens to be successful. Otherwise, we'll always see antigen escape. Q2 AdCAR-T如何有效地针对AML细胞的异质性？这种策略在实际临床应用中的表现如何？ Marion Subklewe教授：在急性髓系白血病的生物学特性中，目标抗原的表达呈现出显著的异质性，这种异质性不仅体现在不同个体间的差异，还深刻影响着同一患者体内不同克隆间的表达模式。具体而言，即便是在同一位AML患者体内，针对同一目标抗原的不同克隆，其表达谱也往往大相径庭。这一特点与CD19 CAR-T细胞疗法所面对的情况形成了鲜明对比。在我看来，若采用适配器方法治疗AML时，我们若仅将治疗焦点局限于单一抗原，则很可能无法实现疾病的根治。在此策略下，我们采用的是通用型CAR-T细胞，其特异性完全依赖于适配器分子的设计与选择。得益于这一设计，我们能够灵活地更换适配器，进而实现对多个抗原同时或依次地靶向。因此，我认为适配器平台的核心优势，在于其为我们提供了前所未有的能力，使我们能够针对AML中复杂多变的抗原表达谱，实施更为精准且全面的治疗策略。（上下滑动查看英文原文） How does AdCAR-T effectively target the heterogeneity of AML cells ? How has this strategy performed in actual clinical applications? We know in AML that the target antigen expression is very heterogeneous, both inter- and intra-individuals. Even patients have different clones with different expression profiles of the same target antigen. So that's very different from the CD19 CAR-T cell field. I don't believe we can cure AML by targeting only one antigen with the adapter approach, where we have a generic CAR-T cell. The specificity is only given by the adapter molecule. We can exchange the adapter and thereby target multiple antigens, either in parallel or sequentially. So I think the big advantage of the adapter platform is that we can target multiple antigens. Q3 在优化急性髓系白血病的CAR-T细胞治疗策略方面，您认为需要全面审视并综合考量哪些关键因素？ Marion Subklewe教授：我认为，在优化急性髓系白血病的CAR-T细胞治疗策略时，必须全面审视并综合考量以下四个关键方面。首先，当前我们在患者已经历三到四种前期治疗，且前期治疗已相当充分的情况下，才考虑引入CAR-T细胞治疗。然而，我们应更积极地探索将双特异性CAR-T细胞及CAR-NK细胞应用于疾病负担较轻的更早期治疗阶段，以期获得更佳疗效。其次，针对抗原逃逸变异体的存在，需要采取多抗原靶向策略。通过同时靶向两个或三个靶抗原，可以更有效地规避抗原逃逸现象，从而提高治疗的成功率。第三，鉴于免疫抑制性微环境对CAR-T细胞治疗的影响，以及《自然医学》最新报道揭示的T细胞分泌细胞因子介导AML细胞抗性的机制，我们需要联合使用如JAK抑制剂等小分子药物，以克服这种抗性。第四，探索与其他免疫策略的结合，如将CAR-T细胞治疗与STING激动剂等先天免疫激活剂联合应用，可能展现出广阔的前景。此外，目前CAR-T细胞之外的治疗策略主要聚焦于两大领域。一方面，鉴于AML遗传学特征的异质性，我们正致力于研究各种遗传类型，并开发具有预后意义的靶向疗法。另一方面，微小残留病（MRD）的监测与管理同样至关重要，包括MRD的应答情况、持续存在状态以及再次转阳的风险。然而，在免疫治疗的背景下，特别是CAR-T细胞治疗的背景下，还必须将肿瘤微环境和骨髓状况作为重要的考量因素。随着不同风险亚组的出现，这一治疗策略将变得更加复杂。我担忧的是，如果根据遗传学、MRD和微环境对患者进行精细分层，每个组别的患者数量将非常有限。因此，我认为传播和发展AML特异性CAR-T细胞的任务主要落在医学研究者的肩上。尽管患者数量有限，但我认为，正如肿瘤学其他领域一样，AML的治疗也必须采取个性化方法。一刀切的治疗策略在此类复杂疾病中注定无法取得成功。（上下滑动查看英文原文） In optimizing CAR-T cell therapy strategies for acute myeloid leukemia (AML), what key factors do you believe need to be comprehensively examined and considered? I think four aspects have to be considered to improve CAR-T cells strategies, or therapy in AML. First of all, we are currently using CAR-T cells in heavily pretreated patients after three or four prior treatment lines. I think we have to move bio-specific CAR-T cells、CAR-NK cells into earlier treatment lines with low disease burden. Second, I think we need to integrate targeting of multiple antigens. We'll see antigen escape variants. So I think targeting two or three target antigens will be more successful. Thirdly, I think, as there is an immunosuppressive microenvironment and a recent report that also T cells secrete cytokines that mediate resistance of AML cells,that has been published in Nature Medicine, we also need to combine, for example, with JAK inhibitors or other small molecules to overcome resistance. And fourthly, other strategies like combining it with strategies of innate immunity like STING agonists could be really promising. I think currently, our strategy, which is now independent of CAR-T cells, is very much focused on two aspects. The genetics of AML is very heterogeneous, and we have some targeted therapies, but it's also prognostic. So we are looking at all the different genetic types. The second really important aspect is MRD, so MRD response, MRD persistence, or turning MRD positive again. But I think in the context of immunotherapy, particularly CAR-T cells, we have to integrate the tumor microenvironment, sort of the health of the bone marrow as a third factor. Unfortunately, it's gonna get more and more complicated with different small risk groups. I'm concerned that this will not be very attractive for industry, because we have really small patient population,if you stratify for genetics, MRD, and the microenvironment. So I think it's really the task of academic medicine to propagate and develop AML specific CAR-T cells. Unfortunately, but I think, like everywhere in oncology, this has to be a personalized approach, although the patient numbers will get really small. But I think one-size-fits-all concepts are not going to work. Q4 能否谈谈您在研究过程中遇到的最大挑战是什么？以及您对未来研究方向的展望？ Marion Subklewe教授：当前，急性髓系白血病的治疗领域主要遵循两大策略。首要策略是运用CAR-T细胞疗法，旨在达成形态学上的白血病完全缓解状态，理想情况下实现MRD阴性，并随后辅以异基因干细胞移植。然而，该策略中CAR-T细胞需被完全清除，故而其疗效局限于一个相对短暂的时间窗口内。尽管如此，此方法仍能有效针对髓系抗原，且避免了造血功能衰竭的风险。另一种极具潜力且持续发展的策略，则是基因编辑的干细胞移植。借助CRISPR/Cas技术，我们能够精准删除靶抗原，这包括整个靶抗原或是仅通过引入非同义突变来移除特定的被靶向表位，随后再引入CAR-T细胞治疗。此策略的一大优势在于，CAR-T细胞能够得以保留并持续发挥作用，从而展现出更持久的活性。因此，我们满怀期待地关注着这一方法未来的临床成效。值得注意的是，截至目前，关于第二种策略的临床试验数据尚未面世。需要注意的是，当前领域内仍面临多重挑战。其中，核心难题之一在于寻觅恰当的靶抗原。当前，广泛采用的靶抗原多为髓系相关抗原，这一事实引发了我们对潜在风险的深切关注：这些抗原可能对健康造血系统产生靶向毒性，甚至诱发其他恶性肿瘤。尽管B细胞的缺失并不致命，且IgG缺乏症可通过IgG替代疗法得到有效管理，从而减轻了这一方面的顾虑，但在髓系细胞层面，情况则截然不同。因此，在AML治疗中精准识别并选定合适的靶抗原，构成了我们面临的一项严峻挑战。此外，AML治疗还面临着另一项重大挑战，即耐药性的显著增强。AML的生物学特性使其更类似于具有免疫抑制性微环境的实体瘤，这无疑增加了治疗的复杂性和难度。其耐药性的产生，复杂地交织着微环境的调控作用以及T细胞与AML细胞间的相互作用。耐药性的存在要求我们不断探索新的治疗策略，以克服这一障碍。鉴于此，我深信未来的治疗策略需更加多元化，可能需要引入其他小分子药物或设计更为精细的预处理方案，以期有效逆转免疫抑制性的微环境，从而为CAR-T细胞疗法创造更为有利的条件。同时，我也认为，单一依赖CAR-T细胞疗法难以达到理想的疗效，必须探索并实施联合治疗的策略，以协同增强治疗效果。因此，如何应对CAR-T细胞疗法在治疗AML中面临的耐药性挑战，无疑是摆在我们面前的一项重大而紧迫的任务。（上下滑动查看英文原文） could you share what the biggest challenge you faced during your research was? And what are your expectations for future research directions? There are two strategies currently being followed in AML. One strategy is applying CAR-T cells, achieving a morphological leukemia-free state, preferentially MRD negative, and followed by an allogeneic stem cell transplantation.And with this approach, you eliminate all the CAR-T cells. You only have the efficacy of the CAR-T cells for a very limited approach.But at least you can target myeloid antigens. And aplasia is not an issue. I think a very interesting evolving strategy is to do edited stem cell grafts. You delete sort of the target antigen by CRISPR/Cas, either the entire target antigen or by creating a non-synonymous mutation, just the epitope that is targeted, followed by CAR-T cells. And there you have the advantage. The CAR-T cells are allowed to persist. They have longer activities. So we'll see how this turns out. And currently, we have no clinical trial data for the second approach yet. One of the major challenges, in particularly in the context of acute myeloid leukemia, is identifying a suitable target antigen. As you are aware, most of the target antigens currently being employed are myeloid lineage antigens. There's a great concern of on-target of leukemia, toxicity on the healthy hemorrhagic system, as you're aware, and some malignancies. This is less of an issue because we can live without b cells and substitute IgG deficiency with IgG replacement therapy. So that is not the case with a myeloid compartment. Identifying suitable target antigen in AML is one of the challenges. The second challenge is that we have more resistance. It's more like a solid tumor with an immunosuppressive microenvironment. These are the two challenges we address in AML. I think besides target antigens and toxicity, another big issue in CAR-T cells and AML is resistance, mediated through the microenvironment and through T-cell, AML interaction. I think future strategies have to implement possibly other small molecules or conditioning regimens to counteract the immunosuppressive microenvironment. I think we will not be able to cure with just a CAR-T cell therapy, but need to adopt combinatory approaches. So, I think this is one of the future challenges we have to tackle. （来源：《肿瘤瞭望–血液时讯》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

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