Pub Date : 2024-09-25DOI: 10.1038/s41375-024-02414-4
Farhad Ravandi, Jayastu Senapati, Nitin Jain, Nicholas J. Short, Tapan Kadia, Gautam Borthakur, Marina Konopleva, William Wierda, Xuelin Huang, Abhishek Maiti, Ghayas Issa, Hayley Balkin, Rebecca Garris, Alessandra Ferrajoli, Guillermo Garcia-Manero, Yesid Alvarado, Partow Kebriaei, Elias Jabbour, Hagop M. Kantarjian
Optimal frontline use of active agents in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is prudent to improve outcomes. We report the long-term follow-up of the phase 2 trial of HyperCVAD with nelarabine and pegylated asparaginase (Original cohort). In the latest protocol iteration venetoclax was added to the induction/consolidation regimen (Venetoclax cohort). Eligible patients were adults with untreated T-ALL/LBL or after minimal therapy and with adequate organ function. Primary endpoint of this analysis was improvement in 2-year progression free survival (PFS) and overall survival (OS) with venetoclax. From Aug 2007 to Dec 2024, 145 patients, at a median age of 35.4 years, were treated; 46 (33.8%) were in the venetoclax cohort. At median follow-up (mFU) of 62.4 months, 5-year PFS, duration of response (DOR), and OS were 63.7%, 72.0% and 66.2% respectively. In the venetoclax cohort (mFU 24.4 months) 2-year PFS (87.9% versus 64.1%, p = 0.03) and 2-year DOR (93.6% versus 69.2%, p = 0.005) were superior to the original cohort (mFU 89.4 months) and 2-year OS appeared better (87.8% versus 73.9%, p = 0.16). Febrile neutropenia was the most common serious adverse event, seen in 60% patients. The addition of venetoclax to HyperCVAD-nelarabine-pegylated asparaginase was tolerable and led to improvement in DOR and PFS.
{"title":"Longitudinal follow up of a phase 2 trial of venetoclax added to hyper-CVAD, nelarabine and pegylated asparaginase in patients with T-cell acute lymphoblastic leukemia and lymphoma","authors":"Farhad Ravandi, Jayastu Senapati, Nitin Jain, Nicholas J. Short, Tapan Kadia, Gautam Borthakur, Marina Konopleva, William Wierda, Xuelin Huang, Abhishek Maiti, Ghayas Issa, Hayley Balkin, Rebecca Garris, Alessandra Ferrajoli, Guillermo Garcia-Manero, Yesid Alvarado, Partow Kebriaei, Elias Jabbour, Hagop M. Kantarjian","doi":"10.1038/s41375-024-02414-4","DOIUrl":"https://doi.org/10.1038/s41375-024-02414-4","url":null,"abstract":"<p>Optimal frontline use of active agents in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is prudent to improve outcomes. We report the long-term follow-up of the phase 2 trial of HyperCVAD with nelarabine and pegylated asparaginase (Original cohort). In the latest protocol iteration venetoclax was added to the induction/consolidation regimen (Venetoclax cohort). Eligible patients were adults with untreated T-ALL/LBL or after minimal therapy and with adequate organ function. Primary endpoint of this analysis was improvement in 2-year progression free survival (PFS) and overall survival (OS) with venetoclax. From Aug 2007 to Dec 2024, 145 patients, at a median age of 35.4 years, were treated; 46 (33.8%) were in the venetoclax cohort. At median follow-up (mFU) of 62.4 months, 5-year PFS, duration of response (DOR), and OS were 63.7%, 72.0% and 66.2% respectively. In the venetoclax cohort (mFU 24.4 months) 2-year PFS (87.9% versus 64.1%, <i>p</i> = 0.03) and 2-year DOR (93.6% versus 69.2%, <i>p</i> = 0.005) were superior to the original cohort (mFU 89.4 months) and 2-year OS appeared better (87.8% versus 73.9%, <i>p</i> = 0.16). Febrile neutropenia was the most common serious adverse event, seen in 60% patients. The addition of venetoclax to HyperCVAD-nelarabine-pegylated asparaginase was tolerable and led to improvement in DOR and PFS.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1038/s41375-024-02404-6
María-Victoria Mateos, Katja Weisel, Valerio De Stefano, Hartmut Goldschmidt, Michel Delforge, Mohamad Mohty, Dominik Dytfeld, Emanuele Angelucci, Laure Vincent, Aurore Perrot, Reuben Benjamin, Niels W. C. J. van de Donk, Enrique M. Ocio, Tito Roccia, Jordan M. Schecter, Silva Koskinen, Imène Haddad, Vadim Strulev, Lada Mitchell, Jozefien Buyze, Octavio Costa Filho, Hermann Einsele, Philippe Moreau
Treatment of relapsed/refractory multiple myeloma (RRMM) is challenging as patients exhaust all available therapies and the disease becomes refractory to standard drug classes. Here we report the final results of LocoMMotion, the first prospective study of real-world clinical practice (RWCP) in triple-class exposed (TCE) patients with RRMM, with a median follow-up of 26.4 months (range, 0.1–35.0). Patients (N = 248) had received median 4 prior LOT (range, 2–13) at enrollment. 91 unique regimens were used in index LOT. Overall response rate was 31.9% (95% CI, 26.1–38.0), median progression-free survival (PFS) was 4.6 months (95% CI, 3.9–5.6) and median overall survival was 13.8 months (95% CI, 10.8–17.0). 152 patients (61.3%) had subsequent LOTs with 134 unique regimens, of which 78 were used in first subsequent LOT. Median PFS2 (from start of study through first subsequent LOT) was 10.8 months (95% CI, 8.4–13.0). 158 patients died on study, 67.7% due to progressive disease. Additional subgroup analyses and long-term safety summaries are reported. The high number of RWCP treatment regimens utilized and poor clinical outcomes confirm a lack of standardized treatment for TCE patients with RRMM, highlighting the need for new treatments with novel mechanisms.
复发性/难治性多发性骨髓瘤(RRMM)的治疗具有挑战性,因为患者用尽了所有可用的疗法,而且疾病对标准药物类别产生了耐药性。在此,我们报告了LocoMMotion的最终结果,这是首个针对暴露于三类药物(TCE)的RRMM患者进行的真实世界临床实践(RWCP)前瞻性研究,中位随访时间为26.4个月(0.1-35.0个月)。患者(N = 248)入组时中位接受过 4 次 LOT 治疗(2-13 次)。指数 LOT 采用了 91 种不同的治疗方案。总反应率为31.9%(95% CI,26.1-38.0),中位无进展生存期(PFS)为4.6个月(95% CI,3.9-5.6),中位总生存期为13.8个月(95% CI,10.8-17.0)。152名患者(61.3%)接受了后续LOT治疗,使用了134种独特的治疗方案,其中78种用于首次后续LOT治疗。中位 PFS2(从研究开始到首次后续治疗)为 10.8 个月(95% CI,8.4-13.0)。158名患者在研究期间死亡,67.7%死于疾病进展。本研究还报告了其他亚组分析和长期安全性总结。使用的RWCP治疗方案较多,临床疗效不佳,这证实了TCE RRMM患者缺乏标准化治疗,突出了对具有新机制的新疗法的需求。
{"title":"LocoMMotion: a study of real-life current standards of care in triple-class exposed patients with relapsed/refractory multiple myeloma – 2-year follow-up (final analysis)","authors":"María-Victoria Mateos, Katja Weisel, Valerio De Stefano, Hartmut Goldschmidt, Michel Delforge, Mohamad Mohty, Dominik Dytfeld, Emanuele Angelucci, Laure Vincent, Aurore Perrot, Reuben Benjamin, Niels W. C. J. van de Donk, Enrique M. Ocio, Tito Roccia, Jordan M. Schecter, Silva Koskinen, Imène Haddad, Vadim Strulev, Lada Mitchell, Jozefien Buyze, Octavio Costa Filho, Hermann Einsele, Philippe Moreau","doi":"10.1038/s41375-024-02404-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02404-6","url":null,"abstract":"<p>Treatment of relapsed/refractory multiple myeloma (RRMM) is challenging as patients exhaust all available therapies and the disease becomes refractory to standard drug classes. Here we report the final results of LocoMMotion, the first prospective study of real-world clinical practice (RWCP) in triple-class exposed (TCE) patients with RRMM, with a median follow-up of 26.4 months (range, 0.1–35.0). Patients (<i>N</i> = 248) had received median 4 prior LOT (range, 2–13) at enrollment. 91 unique regimens were used in index LOT. Overall response rate was 31.9% (95% CI, 26.1–38.0), median progression-free survival (PFS) was 4.6 months (95% CI, 3.9–5.6) and median overall survival was 13.8 months (95% CI, 10.8–17.0). 152 patients (61.3%) had subsequent LOTs with 134 unique regimens, of which 78 were used in first subsequent LOT. Median PFS2 (from start of study through first subsequent LOT) was 10.8 months (95% CI, 8.4–13.0). 158 patients died on study, 67.7% due to progressive disease. Additional subgroup analyses and long-term safety summaries are reported. The high number of RWCP treatment regimens utilized and poor clinical outcomes confirm a lack of standardized treatment for TCE patients with RRMM, highlighting the need for new treatments with novel mechanisms.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1038/s41375-024-02408-2
Justus M. Huelse, Swati S. Bhasin, Kristen M. Jacobsen, Juhye Yim, Beena E. Thomas, Gianna M. Branella, Mojtaba Bakhtiari, Madison L. Chimenti, Travon A. Baxter, Sunil S. Raikar, Xiaodong Wang, Stephen V. Frye, Curtis J. Henry, H. Shelton Earp, Manoj Bhasin, Deborah DeRyckere, Douglas K. Graham
TAM-family tyrosine kinases (TYRO3, AXL and MERTK) are potential cancer therapeutic targets. In previous studies MERTK inhibition in the immune microenvironment was therapeutically effective in a B-cell acute leukemia (B-ALL) model. Here, we probed anti-leukemia immune mechanisms and evaluated roles for TYRO3 and AXL in the leukemia microenvironment. Host Mertk knock-out or MERTK inhibitor MRX-2843 increased CD8α+ dendritic cells (DCs) with enhanced antigen-presentation capacity in the leukemia microenvironment and inhibited leukemogenesis. High MERTK or low DC gene expression were associated with poor prognosis in pediatric ALL patients, indicating the clinical relevance of these findings. MRX-2843 increased CD8+ T-cell numbers and prevented induction of exhaustion markers, implicating a DC – T-cell axis. Indeed, combined depletion of CD8α+ DCs and CD8+ T-cells was required to abrogate anti-leukemia immunity in Mertk–/–mice. Tyro3–/– mice were also protected against B-ALL, implicating TYRO3 as an immunotherapeutic target. In contrast to Mertk–/– mice, Tyro3–/– did not increase CD8α+ DCs with enhanced antigen-presentation capacity and therapeutic activity was less dependent on DCs, indicating a different immune mechanism. Axl–/– did not impact leukemogenesis. These data demonstrate differential TAM kinase roles in the leukemia microenvironment and provide rationale for development of MERTK and/or TYRO3-targeted immunotherapies.
TAM家族酪氨酸激酶(TYRO3、AXL和MERTK)是潜在的癌症治疗靶点。在以前的研究中,抑制免疫微环境中的 MERTK 对 B 细胞急性白血病(B-ALL)模型有治疗效果。在这里,我们探究了抗白血病免疫机制,并评估了 TYRO3 和 AXL 在白血病微环境中的作用。宿主Mertk基因敲除或MERTK抑制剂MRX-2843增加了白血病微环境中抗原呈递能力增强的CD8α+树突状细胞(DC),并抑制了白血病的发生。高MERTK或低DC基因表达与小儿ALL患者的不良预后有关,这表明了这些发现的临床意义。MRX-2843 增加了 CD8+ T 细胞数量,防止了衰竭标志物的诱导,这与 DC - T 细胞轴有关。事实上,需要联合消耗 CD8α+ DCs 和 CD8+ T 细胞才能削弱 Mertk-/- 小鼠的抗白血病免疫力。Tyro3-/-小鼠对B-ALL也有保护作用,这表明TYRO3是一个免疫治疗靶点。与Mertk-/-小鼠相比,Tyro3-/-小鼠没有增加具有增强抗原递呈能力的CD8α+ DCs,治疗活性对DCs的依赖性较低,这表明免疫机制不同。Axl-/-不会影响白血病的发生。这些数据证明了TAM激酶在白血病微环境中的不同作用,并为开发MERTK和/或TYRO3靶向免疫疗法提供了理论依据。
{"title":"MERTK inhibition selectively activates a DC – T-cell axis to provide anti-leukemia immunity","authors":"Justus M. Huelse, Swati S. Bhasin, Kristen M. Jacobsen, Juhye Yim, Beena E. Thomas, Gianna M. Branella, Mojtaba Bakhtiari, Madison L. Chimenti, Travon A. Baxter, Sunil S. Raikar, Xiaodong Wang, Stephen V. Frye, Curtis J. Henry, H. Shelton Earp, Manoj Bhasin, Deborah DeRyckere, Douglas K. Graham","doi":"10.1038/s41375-024-02408-2","DOIUrl":"https://doi.org/10.1038/s41375-024-02408-2","url":null,"abstract":"<p>TAM-family tyrosine kinases (TYRO3, AXL and MERTK) are potential cancer therapeutic targets. In previous studies MERTK inhibition in the immune microenvironment was therapeutically effective in a B-cell acute leukemia (B-ALL) model. Here, we probed anti-leukemia immune mechanisms and evaluated roles for TYRO3 and AXL in the leukemia microenvironment. Host <i>Mertk</i> knock-out or MERTK inhibitor MRX-2843 increased CD8α<sup>+</sup> dendritic cells (DCs) with enhanced antigen-presentation capacity in the leukemia microenvironment and inhibited leukemogenesis. High <i>MERTK</i> or low DC gene expression were associated with poor prognosis in pediatric ALL patients, indicating the clinical relevance of these findings. MRX-2843 increased CD8<sup>+</sup> T-cell numbers and prevented induction of exhaustion markers, implicating a DC – T-cell axis. Indeed, combined depletion of CD8α<sup>+</sup> DCs and CD8<sup>+</sup> T-cells was required to abrogate anti-leukemia immunity in <i>Mertk</i><sup><i>–/–</i></sup> <i>mice</i>. <i>Tyro3</i><sup>–/–</sup> mice were also protected against B-ALL, implicating TYRO3 as an immunotherapeutic target. In contrast to <i>Mertk</i><sup><i>–/–</i></sup> mice, <i>Tyro3</i><sup>–/–</sup> did not increase CD8α<sup>+</sup> DCs with enhanced antigen-presentation capacity and therapeutic activity was less dependent on DCs, indicating a different immune mechanism. <i>Axl</i><sup>–/–</sup> did not impact leukemogenesis. These data demonstrate differential TAM kinase roles in the leukemia microenvironment and provide rationale for development of MERTK and/or TYRO3-targeted immunotherapies.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1038/s41375-024-02419-z
Laura Martinez-Verbo, Yoana Veselinova, Pere Llinàs-Arias, Carlos A. García-Prieto, Aleix Noguera-Castells, Miguel L. Pato, Alberto Bueno-Costa, Ignacio Campillo-Marcos, Lorea Villanueva, Aina Oliver-Caldes, Oriol Cardus, Sergi V. Salsench, Almudena García-Ortiz, Antonio Valeri, Elizabeta A. Rojas, Naroa Barrena, Norma C. Gutiérrez, Felipe Prósper, Xabier Agirre, Carlos Fernández de Larrea, Joaquín Martínez-López, Gerardo Ferrer, Manel Esteller
{"title":"PVR (CD155) epigenetic status mediates immunotherapy response in multiple myeloma","authors":"Laura Martinez-Verbo, Yoana Veselinova, Pere Llinàs-Arias, Carlos A. García-Prieto, Aleix Noguera-Castells, Miguel L. Pato, Alberto Bueno-Costa, Ignacio Campillo-Marcos, Lorea Villanueva, Aina Oliver-Caldes, Oriol Cardus, Sergi V. Salsench, Almudena García-Ortiz, Antonio Valeri, Elizabeta A. Rojas, Naroa Barrena, Norma C. Gutiérrez, Felipe Prósper, Xabier Agirre, Carlos Fernández de Larrea, Joaquín Martínez-López, Gerardo Ferrer, Manel Esteller","doi":"10.1038/s41375-024-02419-z","DOIUrl":"https://doi.org/10.1038/s41375-024-02419-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Whether ibrutinib-related atrial fibrillation (IRAF) is a dose-dependent adverse drug reaction (ADR) and whether ibrutinib should be discontinued or dose-reduced in case of IRAF occurrence remains unknown. Using the World Health Organization individual case safety report pharmacovigilance database, VigiBase®, we aimed to determine the association between ibrutinib dosing regimens and IRAF reporting. Ibrutinib daily dose was extracted from IRAF cases from VigiBase® and was divided into 5 ibrutinib dosing regimen (140-280-420-560 and >560 mg/day). Disproportionality analysis was used to evaluate the association between IRAF reporting and ibrutinib daily dose, through logistic regression. Single term deletions produced the ibrutinib daily dose global p-value. Then, a multivariable adjusted reporting odds-ratio with its 95% confidence interval was calculated for each ibrutinib dosing regimen, against the lowest dosing regimen (140 mg/day) as reference. A total of 1162 IRAF cases were identified in VigiBase® (n = 62 for ibrutinib 140 mg/day, 114 for ibrutinib 280 mg/day, 811 for ibrutinib 420 mg/day, 164 for ibrutinib 560 mg/day and 11 for ibrutinib >560 mg/day). After adjustment on several variables of interest, IRAF reporting was not significantly associated with ibrutinib dosing regimen (p = 0.09). Our results from Vigibase® do not support IRAF as a dose-dependent ADR (ClinicalTrial registration number: NCT06224452).
{"title":"Is ibrutinib-related atrial fibrillation dose dependent? Insights from an individual case level analysis of the World Health Organization pharmacovigilance database.","authors":"Joachim Alexandre,Jonaz Font,Da-Silva Angélique,Baptiste Delapierre,Ghandi Damaj,Anne-Flore Plane,Damien Legallois,Paul Milliez,Charles Dolladille,Basile Chrétien","doi":"10.1038/s41375-024-02413-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02413-5","url":null,"abstract":"Whether ibrutinib-related atrial fibrillation (IRAF) is a dose-dependent adverse drug reaction (ADR) and whether ibrutinib should be discontinued or dose-reduced in case of IRAF occurrence remains unknown. Using the World Health Organization individual case safety report pharmacovigilance database, VigiBase®, we aimed to determine the association between ibrutinib dosing regimens and IRAF reporting. Ibrutinib daily dose was extracted from IRAF cases from VigiBase® and was divided into 5 ibrutinib dosing regimen (140-280-420-560 and >560 mg/day). Disproportionality analysis was used to evaluate the association between IRAF reporting and ibrutinib daily dose, through logistic regression. Single term deletions produced the ibrutinib daily dose global p-value. Then, a multivariable adjusted reporting odds-ratio with its 95% confidence interval was calculated for each ibrutinib dosing regimen, against the lowest dosing regimen (140 mg/day) as reference. A total of 1162 IRAF cases were identified in VigiBase® (n = 62 for ibrutinib 140 mg/day, 114 for ibrutinib 280 mg/day, 811 for ibrutinib 420 mg/day, 164 for ibrutinib 560 mg/day and 11 for ibrutinib >560 mg/day). After adjustment on several variables of interest, IRAF reporting was not significantly associated with ibrutinib dosing regimen (p = 0.09). Our results from Vigibase® do not support IRAF as a dose-dependent ADR (ClinicalTrial registration number: NCT06224452).","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1038/s41375-024-02409-1
Laura Volta, Renier Myburgh, Christian Pellegrino, Christian Koch, Monique Maurer, Francesco Manfredi, Mara Hofstetter, Anne Kaiser, Florin Schneiter, Jan Müller, Marco M. Buehler, Roberto De Luca, Nicholas Favalli, Chiara F. Magnani, Timm Schroeder, Dario Neri, Markus G. Manz
CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.
CAR T 细胞产品靶向特定系的原发细胞抗原,从而消除肿瘤细胞和健康的对应细胞,是目前临床上批准的治疗 B 细胞和浆细胞恶性肿瘤的疗法。虽然它们在临床上取得了重大进展,但在疗效方面仍受到限制,例如只能靶向单一抗原,有时甚至是低表达抗原;在安全性方面也受到限制,例如缺乏开关活性。要成功地对异质性造血干细胞和祖细胞恶性肿瘤(如急性髓性白血病(AML))进行原代细胞非歧视性靶向治疗,需要抗原多变性靶向和效应物的关闭开关,这样才能通过造血干细胞移植(HSCT)进行救治,防止永久性髓细胞消减。为此,我们开发了以荧光AML抗原结合二抗体适配体为靶点的适配体-CAR(AdFITC-CAR)T细胞。这一平台可以使用与 AML 抗原表达谱相匹配的适配体,并进行条件性活性调节。结合适配体可大大提高体外急性髓细胞白血病细胞的裂解率。在治疗性异种小鼠模型中,与单个二抗体适配体共同给药的 AdFITC-CAR T 细胞与直接给药的 CAR T 细胞一样有效,而适配体的组合使用进一步提高了对细胞系和原发性 AML 的疗效。总之,这项研究提供了概念证明,即 AdFITC-CAR T 细胞和适配体组合能有效增强对急性髓细胞白血病的免疫靶向作用。
{"title":"Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells","authors":"Laura Volta, Renier Myburgh, Christian Pellegrino, Christian Koch, Monique Maurer, Francesco Manfredi, Mara Hofstetter, Anne Kaiser, Florin Schneiter, Jan Müller, Marco M. Buehler, Roberto De Luca, Nicholas Favalli, Chiara F. Magnani, Timm Schroeder, Dario Neri, Markus G. Manz","doi":"10.1038/s41375-024-02409-1","DOIUrl":"https://doi.org/10.1038/s41375-024-02409-1","url":null,"abstract":"<p>CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1038/s41375-024-02412-6
Ekaterina Chelysheva, Jane Apperley, Anna Turkina, Mohamed A Yassin, Delphine Rea, Franck E Nicolini, Daniela Barraco, Khamida Kazakbaeva, Sukhrob Saliev, Adi Shacham Abulafia, Salam Al-Kindi, Jennifer Byrne, Harry F Robertson, Marco Cerrano, Roman Shmakov, Evgenia Polushkina, Paolo de Fabritiis, Malgorzata Monika Trawinska, Elisabetta Abruzzese
{"title":"Correction: Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry.","authors":"Ekaterina Chelysheva, Jane Apperley, Anna Turkina, Mohamed A Yassin, Delphine Rea, Franck E Nicolini, Daniela Barraco, Khamida Kazakbaeva, Sukhrob Saliev, Adi Shacham Abulafia, Salam Al-Kindi, Jennifer Byrne, Harry F Robertson, Marco Cerrano, Roman Shmakov, Evgenia Polushkina, Paolo de Fabritiis, Malgorzata Monika Trawinska, Elisabetta Abruzzese","doi":"10.1038/s41375-024-02412-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02412-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1038/s41375-024-02405-5
Melisa Halilovic, Mohamed Abdelsalam, Joanna Zabkiewicz, Michelle Lazenby, Caroline Alvares, Matthias Schmidt, Walburgis Brenner, Sara Najafi, Ina Oehme, Christoph Hieber, Yanira Zeyn, Matthias Bros, Wolfgang Sippl, Oliver H. Krämer
Internal tandem duplications in the FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (p < 0.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a Danio rerio model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (p < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (p < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit.
{"title":"Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins","authors":"Melisa Halilovic, Mohamed Abdelsalam, Joanna Zabkiewicz, Michelle Lazenby, Caroline Alvares, Matthias Schmidt, Walburgis Brenner, Sara Najafi, Ina Oehme, Christoph Hieber, Yanira Zeyn, Matthias Bros, Wolfgang Sippl, Oliver H. Krämer","doi":"10.1038/s41375-024-02405-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02405-5","url":null,"abstract":"<p>Internal tandem duplications in the FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (<i>p</i> < 0.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a <i>Danio rerio</i> model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (<i>p</i> < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (<i>p</i> < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1038/s41375-024-02411-7
Andrew J. Innes, Chloe Hayden, Victoria Orovboni, Simone Claudiani, Fiona Fernando, Afzal Khan, David Rees, Jennifer Byrne, Paolo Gallipoli, Sebastian Francis, Mhairi Copland, Gillian Horne, Manoj Raghavan, Claire Arnold, Angela Collins, Tanya Cranfield, Nicholas Cunningham, Akila Danga, Peter Forsyth, Rebecca Frewin, Paula Garland, Guy Hannah, Daniele Avenoso, Sandra Hassan, Brian J. P. Huntly, Jissan Husain, Sudhakaran Makkuni, Kate Rothwell, Jamshid Khorashad, Jane F. Apperley, Dragana Milojkovic
Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.
{"title":"Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy","authors":"Andrew J. Innes, Chloe Hayden, Victoria Orovboni, Simone Claudiani, Fiona Fernando, Afzal Khan, David Rees, Jennifer Byrne, Paolo Gallipoli, Sebastian Francis, Mhairi Copland, Gillian Horne, Manoj Raghavan, Claire Arnold, Angela Collins, Tanya Cranfield, Nicholas Cunningham, Akila Danga, Peter Forsyth, Rebecca Frewin, Paula Garland, Guy Hannah, Daniele Avenoso, Sandra Hassan, Brian J. P. Huntly, Jissan Husain, Sudhakaran Makkuni, Kate Rothwell, Jamshid Khorashad, Jane F. Apperley, Dragana Milojkovic","doi":"10.1038/s41375-024-02411-7","DOIUrl":"https://doi.org/10.1038/s41375-024-02411-7","url":null,"abstract":"<p>Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-<i>BCR::ABL1</i> single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}