Since the United States Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy in 2017, it has marked a major breakthrough in cancer treatment, leading to a surge in global research and applications in this field. In recent years, China has made rapid progress, quickly catching up through heavy investment in CAR-T construction, preparation processes, and treatment strategies. China’s CAR-T therapy market is driven by substantial pharmaceutical investment targeting its vast population, yet high therapy costs remain uncovered by basic medical insurance. In November 2023, FDA issued a warning about the risk of secondary cancers in patients undergoing CAR-T therapy, sparking global concern. In fact, the China National Medical Products Administration (NMPA) preemptively implemented a series of measures to address the safety concerns of CAR-T therapy, emphasizing the risk of secondary cancers and advising lifelong monitoring as part of the approval process for CAR-T products. Nevertheless, additional regulatory measures are needed to address emerging risks, particularly the threat of secondary cancers. The authors believe that raising the standards for Investigational New Drug (IND) approval and establishing a dynamic reporting and feedback system based on real-world data will strengthen regulatory oversight and support the sustainable growth of the CAR-T industry in China.
{"title":"Redefining chimeric antigen receptor T-cell (CAR-T) regulation: China’s responses to address secondary cancer risks of CAR-T therapy","authors":"Ruirong Tan, Rui Li, Meng-Yuan Dai, Miao Liu, Junning Zhao","doi":"10.1186/s13045-024-01602-0","DOIUrl":"https://doi.org/10.1186/s13045-024-01602-0","url":null,"abstract":"Since the United States Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy in 2017, it has marked a major breakthrough in cancer treatment, leading to a surge in global research and applications in this field. In recent years, China has made rapid progress, quickly catching up through heavy investment in CAR-T construction, preparation processes, and treatment strategies. China’s CAR-T therapy market is driven by substantial pharmaceutical investment targeting its vast population, yet high therapy costs remain uncovered by basic medical insurance. In November 2023, FDA issued a warning about the risk of secondary cancers in patients undergoing CAR-T therapy, sparking global concern. In fact, the China National Medical Products Administration (NMPA) preemptively implemented a series of measures to address the safety concerns of CAR-T therapy, emphasizing the risk of secondary cancers and advising lifelong monitoring as part of the approval process for CAR-T products. Nevertheless, additional regulatory measures are needed to address emerging risks, particularly the threat of secondary cancers. The authors believe that raising the standards for Investigational New Drug (IND) approval and establishing a dynamic reporting and feedback system based on real-world data will strengthen regulatory oversight and support the sustainable growth of the CAR-T industry in China.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"8 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385534","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 : 2024-09-29DOI: 10.1186/s13045-024-01609-7
Esther Redin, Harsha Sridhar, Yingqian A. Zhan, Barbara Pereira Mello, Hong Zhong, Vidushi Durani, Amin Sabet, Parvathy Manoj, Irina Linkov, Juan Qiu, Richard P. Koche, Elisa de Stanchina, Maider Astorkia, Doron Betel, Álvaro Quintanal-Villalonga, Charles M. Rudin
<p><b>Correction: Journal of Hematology & Oncology (2024) 17:58 </b><b>https://doi.org/10.1186/s13045-024-01572-3</b></p><br/><p>The original article mistakenly omitted numerous elements from the article figures due to an error in transferring the files at the proofing stage. The figures have since been updated to restore all missing elements of each affected figure (Figs. 1, 2, 3, 4, 5, 6).</p><figure><figcaption><b data-test="figure-caption-text">Fig. 1</b></figcaption><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13045-024-01609-7/MediaObjects/13045_2024_1609_Fig1_HTML.png?as=webp" type="image/webp"/><img alt="figure 1" aria-describedby="Fig1" height="717" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13045-024-01609-7/MediaObjects/13045_2024_1609_Fig1_HTML.png" width="685"/></picture><p><i>SMARCA4</i> expression correlates with NE features in SCLC.<b> A</b> <i>SMARCA4</i> mRNA levels in cell lines derived from 30 tumor types assessed using the Cancer Cell Line Encyclopedia (CCLE). Bars indicate the median expression per tumor type. <b>B</b> <i>SMARCA4</i> mRNA levels in LUAD and SCLC specimens retrieved from Quintanal Villalonga et al. [27]. Student’s two-tailed unpaired t test. **<i>p</i> < 0.01. <b>C</b> Spearman correlation of <i>SYP, CHGA, INSM1, YAP1</i> and <i>REST</i> with <i>SMARCA4</i> mRNA levels in Rudin et al. and George et al. databases and CCLE[25, 26]. <b>D</b> <i>SMARCA4</i> mRNA expression in low and high NE SCLC tumors in cell lines (CCLE) and clinical specimens (Rudin et al. and George et al.) [25, 26]. One-way ANOVA test followed by Bonferroni post-hoc test. ****<i>p</i> < 0.0001, ***<i>p</i> < 0.001, **<i>p</i> < 0.01. <b>E</b> Western blotting of ASCL1, NEUROD1, SYP and CHGA in isogenic cell lines derived from H82 and H146 expressing different combinations of shRNAs against <i>SMARCA4</i> and/or <i>SMARCA2</i>. Expression of shRNAs from <b>E</b> was conditional of doxycycline treatment. Protein collection and blotting was performed after 14 days of doxycycline treatment. See also Fig. S1</p><span>Full size image</span><svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-chevron-right-small" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></figure><figure><figcaption><b data-test="figure-caption-text">Fig. 2</b></figcaption><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13045-024-01609-7/MediaObjects/13045_2024_1609_Fig2_HTML.png?as=webp" type="image/webp"/><img alt="figure 2" aria-describedby="Fig2" height="995" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13045-024-01609-7/MediaObjects/13045_2024_1609_Fig2_HTML.png" width="685"/></picture><p>SMARCA4 inhibition suppresses the NE phenotype in SCLC. <b>A</b> Hockey-stick plots of DEGs in FHD-286-treated cells
{"title":"Correction: SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing","authors":"Esther Redin, Harsha Sridhar, Yingqian A. Zhan, Barbara Pereira Mello, Hong Zhong, Vidushi Durani, Amin Sabet, Parvathy Manoj, Irina Linkov, Juan Qiu, Richard P. Koche, Elisa de Stanchina, Maider Astorkia, Doron Betel, Álvaro Quintanal-Villalonga, Charles M. Rudin","doi":"10.1186/s13045-024-01609-7","DOIUrl":"https://doi.org/10.1186/s13045-024-01609-7","url":null,"abstract":"<p><b>Correction: Journal of Hematology & Oncology (2024) 17:58 </b><b>https://doi.org/10.1186/s13045-024-01572-3</b></p><br/><p>The original article mistakenly omitted numerous elements from the article figures due to an error in transferring the files at the proofing stage. The figures have since been updated to restore all missing elements of each affected figure (Figs. 1, 2, 3, 4, 5, 6).</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13045-024-01609-7/MediaObjects/13045_2024_1609_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"717\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13045-024-01609-7/MediaObjects/13045_2024_1609_Fig1_HTML.png\" width=\"685\"/></picture><p><i>SMARCA4</i> expression correlates with NE features in SCLC.<b> A</b> <i>SMARCA4</i> mRNA levels in cell lines derived from 30 tumor types assessed using the Cancer Cell Line Encyclopedia (CCLE). Bars indicate the median expression per tumor type. <b>B</b> <i>SMARCA4</i> mRNA levels in LUAD and SCLC specimens retrieved from Quintanal Villalonga et al. [27]. Student’s two-tailed unpaired t test. **<i>p</i> < 0.01. <b>C</b> Spearman correlation of <i>SYP, CHGA, INSM1, YAP1</i> and <i>REST</i> with <i>SMARCA4</i> mRNA levels in Rudin et al. and George et al. databases and CCLE[25, 26]. <b>D</b> <i>SMARCA4</i> mRNA expression in low and high NE SCLC tumors in cell lines (CCLE) and clinical specimens (Rudin et al. and George et al.) [25, 26]. One-way ANOVA test followed by Bonferroni post-hoc test. ****<i>p</i> < 0.0001, ***<i>p</i> < 0.001, **<i>p</i> < 0.01. <b>E</b> Western blotting of ASCL1, NEUROD1, SYP and CHGA in isogenic cell lines derived from H82 and H146 expressing different combinations of shRNAs against <i>SMARCA4</i> and/or <i>SMARCA2</i>. Expression of shRNAs from <b>E</b> was conditional of doxycycline treatment. Protein collection and blotting was performed after 14 days of doxycycline treatment. See also Fig. S1</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 2</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13045-024-01609-7/MediaObjects/13045_2024_1609_Fig2_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 2\" aria-describedby=\"Fig2\" height=\"995\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13045-024-01609-7/MediaObjects/13045_2024_1609_Fig2_HTML.png\" width=\"685\"/></picture><p>SMARCA4 inhibition suppresses the NE phenotype in SCLC. <b>A</b> Hockey-stick plots of DEGs in FHD-286-treated cells","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"22 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329898","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}
Given its nearly ubiquitous expression on plasma cells and limited expression on essential normal tissue, the G protein-coupled receptor class C group 5 member D (GPRC5D) presents a promising opportunity for utilization as an immunotherapy target in multiple myeloma (MM). The therapeutic strategies targeting GPRC5D, such as bispecific antibodies (BsAbs), chimeric antigen receptor (CAR) T cells, and antibody–drug conjugates (ADCs), have been prominently emphasized in relapsed/refractory MM (R/R MM) in recent years. Further clinical trials are necessary to confirm the long-term efficacy of GPRC5D-targeting immunotherapies alone, explore their potentials co-targeting with other specific antigens, or investigate their combinations with existing treatments to overcome MM resistance. This review provides an overview of current research progress in GPRC5D, encompassing its biological characteristics and translational journey from laboratory to clinical application.
鉴于GPRC5D在浆细胞中的表达几乎无处不在，而在重要的正常组织中表达有限，因此G蛋白偶联受体C类5成员D（GPRC5D）有望被用作多发性骨髓瘤（MM）的免疫疗法靶点。近年来，针对GPRC5D的治疗策略，如双特异性抗体（BsAbs）、嵌合抗原受体（CAR）T细胞和抗体药物共轭物（ADCs）等，在复发/难治性MM（R/R MM）中受到了高度重视。有必要开展进一步的临床试验，以确认 GPRC5D 靶向免疫疗法单独使用的长期疗效，探索其与其他特异性抗原联合靶向的潜力，或研究其与现有治疗方法的组合，以克服 MM 的耐药性。本综述概述了 GPRC5D 目前的研究进展，包括其生物学特性以及从实验室到临床应用的转化过程。
{"title":"Targeting GPRC5D for multiple myeloma therapy","authors":"Dian Zhou, Ying Wang, Chong Chen, Zhenyu Li, Kailin Xu, Kai Zhao","doi":"10.1186/s13045-024-01611-z","DOIUrl":"https://doi.org/10.1186/s13045-024-01611-z","url":null,"abstract":"Given its nearly ubiquitous expression on plasma cells and limited expression on essential normal tissue, the G protein-coupled receptor class C group 5 member D (GPRC5D) presents a promising opportunity for utilization as an immunotherapy target in multiple myeloma (MM). The therapeutic strategies targeting GPRC5D, such as bispecific antibodies (BsAbs), chimeric antigen receptor (CAR) T cells, and antibody–drug conjugates (ADCs), have been prominently emphasized in relapsed/refractory MM (R/R MM) in recent years. Further clinical trials are necessary to confirm the long-term efficacy of GPRC5D-targeting immunotherapies alone, explore their potentials co-targeting with other specific antigens, or investigate their combinations with existing treatments to overcome MM resistance. This review provides an overview of current research progress in GPRC5D, encompassing its biological characteristics and translational journey from laboratory to clinical application.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"10 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328694","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 : 2024-09-27DOI: 10.1186/s13045-024-01607-9
Naomi Kawashima, Yasuo Kubota, Carlos Bravo-Perez, Luca Guarnera, Nakisha D. Williams, Arda Durmaz, Michaela Witt, Arooj Ahmed, Carmelo Gurnari, Jaroslaw P. Maciejewski, Valeria Visconte
DNA methyltransferase 3 A mutations (DNMT3AMT) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3AMT can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3AMT identified out of 5,603 consecutive MNs, of whom 8.4% had multiple DNMT3AMT hits. They were most frequent in acute myeloid leukemia (AML) with R882 variant accounting for 13.3% of the multi-hits. Multiple DNMT3AMT more likely coincided with IDH2 (P = 0.005) and ETV6 (P = 0.044) mutations compared to patients with single DNMT3AMT. When the sum of variant allele frequencies (VAFs) for multiple DNMT3AMT exceeded 60%, we found a significant positive clonal burden correlation of the two DNMT3A variants (P < 0.0001) suggesting that they occurred in biallelic configuration. AML patients with biallelic DNMT3A inactivation (n = 52) presented with older age (P = 0.029), higher leukocytes (P < 0.0001) and peripheral blast counts (P = 0.0001) and significantly poorer survival rate (5.6% vs. 47.6% at 2 years; P = 0.002) than monoallelic DNMT3AMT. Multivariate analysis identified biallelic DNMT3AMT (HR 2.65; P = 0.001), male gender (HR 2.05; P = 0.014) and adverse genetic alteration according to the European LeukemiaNet 2022 classification (HR 1.84; P = 0.028) as independent adverse factors for survival, whereas intensive chemotherapy (HR 0.47; P = 0.011) favorably influenced outcomes. Longitudinal molecular analysis of 12 cases with biallelic DNMT3AMT demonstrated that such clones persisted or expanded in 9 relapsed or transformed cases (75%) suggesting the early origin of biallelic hits with strong leukemogenic potential. Our study describes the likelihood that biallelic DNMT3AMT, while rare, are indeed compatible with clonal expansion and thus questions the applicability of synthetic lethality strategies.
{"title":"Landscape of biallelic DNMT3A mutant myeloid neoplasms","authors":"Naomi Kawashima, Yasuo Kubota, Carlos Bravo-Perez, Luca Guarnera, Nakisha D. Williams, Arda Durmaz, Michaela Witt, Arooj Ahmed, Carmelo Gurnari, Jaroslaw P. Maciejewski, Valeria Visconte","doi":"10.1186/s13045-024-01607-9","DOIUrl":"https://doi.org/10.1186/s13045-024-01607-9","url":null,"abstract":"DNA methyltransferase 3 A mutations (DNMT3AMT) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3AMT can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3AMT identified out of 5,603 consecutive MNs, of whom 8.4% had multiple DNMT3AMT hits. They were most frequent in acute myeloid leukemia (AML) with R882 variant accounting for 13.3% of the multi-hits. Multiple DNMT3AMT more likely coincided with IDH2 (P = 0.005) and ETV6 (P = 0.044) mutations compared to patients with single DNMT3AMT. When the sum of variant allele frequencies (VAFs) for multiple DNMT3AMT exceeded 60%, we found a significant positive clonal burden correlation of the two DNMT3A variants (P < 0.0001) suggesting that they occurred in biallelic configuration. AML patients with biallelic DNMT3A inactivation (n = 52) presented with older age (P = 0.029), higher leukocytes (P < 0.0001) and peripheral blast counts (P = 0.0001) and significantly poorer survival rate (5.6% vs. 47.6% at 2 years; P = 0.002) than monoallelic DNMT3AMT. Multivariate analysis identified biallelic DNMT3AMT (HR 2.65; P = 0.001), male gender (HR 2.05; P = 0.014) and adverse genetic alteration according to the European LeukemiaNet 2022 classification (HR 1.84; P = 0.028) as independent adverse factors for survival, whereas intensive chemotherapy (HR 0.47; P = 0.011) favorably influenced outcomes. Longitudinal molecular analysis of 12 cases with biallelic DNMT3AMT demonstrated that such clones persisted or expanded in 9 relapsed or transformed cases (75%) suggesting the early origin of biallelic hits with strong leukemogenic potential. Our study describes the likelihood that biallelic DNMT3AMT, while rare, are indeed compatible with clonal expansion and thus questions the applicability of synthetic lethality strategies.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"53 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328770","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}
BACKGROUNDResults of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy.METHODSPatients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle.RESULTSTwenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively.CONCLUSIONTargeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing.TRIAL REGISTRATIONNCT04446962.
{"title":"Phase IB part of LOC-R01, a LOC network non-comparative randomized phase IB/II study testing R-MPV in combination with escalating doses of lenalidomide or ibrutinib for newly diagnosed primary central nervous system lymphoma (PCNSL) patients.","authors":"Alcantara Marion,Chevrier Marion,Jardin Fabrice,Schmitt Anna,Houillier Caroline,Oberic Lucie,Chinot Olivier,Morschhauser Franck,Peyrade Frédéric,Houot Roch,Hoang-Xuan Khê,Ghesquieres Hervé,Soussain Carole","doi":"10.1186/s13045-024-01606-w","DOIUrl":"https://doi.org/10.1186/s13045-024-01606-w","url":null,"abstract":"BACKGROUNDResults of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy.METHODSPatients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle.RESULTSTwenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively.CONCLUSIONTargeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing.TRIAL REGISTRATIONNCT04446962.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"190 1","pages":"86"},"PeriodicalIF":28.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273463","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 : 2024-09-16DOI: 10.1186/s13045-024-01604-y
David Sedloev, Qian Chen, Julia M. Unglaub, Nicola Schanda, Yao Hao, Eleni Besiridou, Brigitte Neuber, Anita Schmitt, Simon Raffel, Yi Liu, Maike Janssen, Carsten Müller-Tidow, Michael Schmitt, Tim Sauer
Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous T cells and the extended time for generation of patient specific CAR T cells. Allogeneic NK cell therapy is a promising alternative, but strategies to enhance efficacy and persistence may be necessary. Proteasome inhibitors (PI) induce changes in the surface proteome which may render malignant cells more vulnerable to NK mediated cytotoxicity. Here, we investigated the potential benefit of combining PIs with CAR-expressing allogeneic NK cells against AML. We established the IC50 concentrations for Bortezomib and Carfilzomib against several AML cell lines. Surface expression of class-I HLA molecules and stress-associated proteins upon treatment with proteasome inhibitors was determined by multiparameter flow cytometry. Using functional in vitro assays, we explored the therapeutic synergy between pre-treatment with PIs and the anti-leukemic efficacy of NK cells with or without expression of AML-specific CAR constructs against AML cell lines and primary patient samples. Also, we investigated the tolerability and efficacy of a single PI application strategy followed by (CAR-) NK cell infusion in two different murine xenograft models of AML. AML cell lines and primary AML patient samples were susceptible to Bortezomib and Carfilzomib mediated cytotoxicity. Conditioned resistance to Azacitidine/Venetoclax did not confer primary resistance to PIs. Treating AML cells with PIs reduced the surface expression of class-I HLA molecules on AML cells in a time-and-dose dependent manner. Stress-associated proteins were upregulated on the transcriptional level and on the cell surface. NK cell mediated killing of AML cells was enhanced in a synergistic manner. PI pre-treatment increased effector-target cell conjugate formation and Interferon-γ secretion, resulting in enhanced NK cell activity against AML cell lines and primary samples in vitro. Expression of CD33- and CD70-specific CARs further improved the antileukemic efficacy. In vivo, Bortezomib pre-treatment followed by CAR-NK cell infusion reduced AML growth, leading to prolonged overall survival. PIs enhance the anti-leukemic efficacy of CAR-expressing allogeneic NK cells against AML in vitro and in vivo, warranting further exploration of this combinatorial treatment within early phase clinical trials.
复发性和难治性急性髓性白血病（AML）的预后很差。CAR T细胞对急性髓性白血病的疗效有限，部分原因是自体T细胞功能失调，以及患者特异性CAR T细胞的生成时间延长。异体 NK 细胞疗法是一种很有前景的替代疗法，但可能需要采取一些策略来提高疗效和持久性。蛋白酶体抑制剂（PI）会诱导表面蛋白质组发生变化，这可能会使恶性细胞更容易受到 NK 介导的细胞毒性的影响。在此，我们研究了将蛋白酶抑制剂与 CAR 表达的异体 NK 细胞结合治疗急性髓细胞性白血病的潜在益处。我们确定了硼替佐米和卡非佐米对几种急性髓细胞白血病细胞系的 IC50 浓度。多参数流式细胞术测定了蛋白酶体抑制剂处理后I类HLA分子和应激相关蛋白的表面表达。利用功能性体外试验，我们探索了PIs预处理与表达或不表达AML特异性CAR构建体的NK细胞对AML细胞系和原发性患者样本的抗白血病疗效之间的协同作用。此外，我们还研究了在两种不同的急性髓细胞白血病小鼠异种移植模型中应用单一 PI 策略，然后输注（CAR-）NK 细胞的耐受性和疗效。急性髓细胞白血病细胞系和原发性急性髓细胞白血病患者样本对硼替佐米和卡非佐米介导的细胞毒性易感。对阿扎胞苷/Venetoclax的条件耐药性不会产生对PIs的原发性耐药性。用PIs治疗急性髓细胞性白血病细胞可减少急性髓细胞性白血病细胞表面I类HLA分子的表达，这种表达具有时间和剂量依赖性。应激相关蛋白在转录水平和细胞表面上调。NK 细胞介导的对 AML 细胞的杀伤以协同方式得到增强。PI预处理增加了效应细胞-靶细胞共轭物的形成和干扰素-γ的分泌，从而增强了NK细胞在体外对AML细胞系和原代样本的活性。CD33和CD70特异性CAR的表达进一步提高了抗白血病的疗效。在体内，硼替佐米（Bortezomib）预处理后输注 CAR-NK 细胞可减少急性髓细胞白血病的生长，从而延长总生存期。PIs增强了CAR表达的异体NK细胞在体外和体内对AML的抗白血病疗效，值得在早期临床试验中进一步探索这种组合疗法。
{"title":"Proteasome inhibition enhances the anti-leukemic efficacy of chimeric antigen receptor (CAR) expressing NK cells against acute myeloid leukemia","authors":"David Sedloev, Qian Chen, Julia M. Unglaub, Nicola Schanda, Yao Hao, Eleni Besiridou, Brigitte Neuber, Anita Schmitt, Simon Raffel, Yi Liu, Maike Janssen, Carsten Müller-Tidow, Michael Schmitt, Tim Sauer","doi":"10.1186/s13045-024-01604-y","DOIUrl":"https://doi.org/10.1186/s13045-024-01604-y","url":null,"abstract":"Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous T cells and the extended time for generation of patient specific CAR T cells. Allogeneic NK cell therapy is a promising alternative, but strategies to enhance efficacy and persistence may be necessary. Proteasome inhibitors (PI) induce changes in the surface proteome which may render malignant cells more vulnerable to NK mediated cytotoxicity. Here, we investigated the potential benefit of combining PIs with CAR-expressing allogeneic NK cells against AML. We established the IC50 concentrations for Bortezomib and Carfilzomib against several AML cell lines. Surface expression of class-I HLA molecules and stress-associated proteins upon treatment with proteasome inhibitors was determined by multiparameter flow cytometry. Using functional in vitro assays, we explored the therapeutic synergy between pre-treatment with PIs and the anti-leukemic efficacy of NK cells with or without expression of AML-specific CAR constructs against AML cell lines and primary patient samples. Also, we investigated the tolerability and efficacy of a single PI application strategy followed by (CAR-) NK cell infusion in two different murine xenograft models of AML. AML cell lines and primary AML patient samples were susceptible to Bortezomib and Carfilzomib mediated cytotoxicity. Conditioned resistance to Azacitidine/Venetoclax did not confer primary resistance to PIs. Treating AML cells with PIs reduced the surface expression of class-I HLA molecules on AML cells in a time-and-dose dependent manner. Stress-associated proteins were upregulated on the transcriptional level and on the cell surface. NK cell mediated killing of AML cells was enhanced in a synergistic manner. PI pre-treatment increased effector-target cell conjugate formation and Interferon-γ secretion, resulting in enhanced NK cell activity against AML cell lines and primary samples in vitro. Expression of CD33- and CD70-specific CARs further improved the antileukemic efficacy. In vivo, Bortezomib pre-treatment followed by CAR-NK cell infusion reduced AML growth, leading to prolonged overall survival. PIs enhance the anti-leukemic efficacy of CAR-expressing allogeneic NK cells against AML in vitro and in vivo, warranting further exploration of this combinatorial treatment within early phase clinical trials.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"7 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234454","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 : 2024-09-13DOI: 10.1186/s13045-024-01587-w
Di Liu, Leilei Wu, Xiaoling Xu, Shuangyan Yang, Ming Liu, Min Hu, Shengxiang Ren, Yaping Xu
Combination of immunotherapy with radiotherapy is under active investigation. The PACIFIC trial firmly established the treatment paradigm of consolidation immunotherapy following definitive chemoradiotherapy, inspiring a series of similar or exploratory combination regimens. This summary highlighted six reports updated in the 2024 ASCO Annual Meeting.
{"title":"Regimens combining radiation and immunotherapy for cancer: latest updates from 2024 ASCO Annual Meeting","authors":"Di Liu, Leilei Wu, Xiaoling Xu, Shuangyan Yang, Ming Liu, Min Hu, Shengxiang Ren, Yaping Xu","doi":"10.1186/s13045-024-01587-w","DOIUrl":"https://doi.org/10.1186/s13045-024-01587-w","url":null,"abstract":"Combination of immunotherapy with radiotherapy is under active investigation. The PACIFIC trial firmly established the treatment paradigm of consolidation immunotherapy following definitive chemoradiotherapy, inspiring a series of similar or exploratory combination regimens. This summary highlighted six reports updated in the 2024 ASCO Annual Meeting.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"34 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174614","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}
Macrophage-based cell therapy is promising in solid tumors, but the efficient acquisition of macrophages remains a challenge. Induced pluripotent stem cell (iPSC)-induced macrophages are a valuable source, but time-consuming and costly. The application of reprogramming technologies allows for the generation of macrophages from somatic cells, thereby facilitating the advancement of cell-based therapies for numerous malignant diseases. The composition of CD45+ myeloid-like cell complex (MCC) and induced macrophage (iMac) were analyzed by flow cytometry and single-cell RNA sequencing. The engraftment capacity of CD45+ MCC was evaluated by two transplantation assays. Regulation of c-Myc on MafB was evaluated by ChIP-qPCR and promoter reporter and dual luciferase assays. The phenotype and phagocytosis of iMac were explored by flow cytometry and immunofluorescence. Leukemia, breast cancer, and patient-derived tumor xenograft models were used to explore the anti-tumor function of iMac. Here we report on the establishment of a novel methodology allowing for reprogramming fibroblasts into functional macrophages with phagocytic activity by c-Myc overexpression. Fibroblasts with ectopic expression of c-Myc in iPSC medium rapidly generated CD45+ MCC intermediates with engraftment capacity as well as the repopulation of distinct hematopoietic compartments. MCC intermediates were stably maintained in iPSC medium and continuously generated functional and highly pure iMac just by M-CSF cytokine stimulation. Single-cell transcriptomic analysis of MCC intermediates revealed that c-Myc up-regulated the expression of MafB, a major regulator of macrophage differentiation, to promote macrophage differentiation. Characterization of the iMac activity showed NF-κB signaling activation and a pro-inflammatory phenotype. iMac cells displayed significantly increased in vivo persistence and inhibition of tumor progression in leukemia, breast cancer, and patient-derived tumor xenograft models. Our findings demonstrate that c-Myc alone is enough to reprogram fibroblasts into functional macrophages, supporting that c-Myc reprogramming strategy of fibroblasts can help circumvent long-standing obstacles to gaining “off-the-shelf” macrophages for anti-cancer immunotherapy.
{"title":"c-Myc alone is enough to reprogram fibroblasts into functional macrophages","authors":"Shanshan Li, Guoyu Chen, Xia Huang, Yingwen Zhang, Shuhong Shen, Haizhong Feng, Yanxin Li","doi":"10.1186/s13045-024-01605-x","DOIUrl":"https://doi.org/10.1186/s13045-024-01605-x","url":null,"abstract":"Macrophage-based cell therapy is promising in solid tumors, but the efficient acquisition of macrophages remains a challenge. Induced pluripotent stem cell (iPSC)-induced macrophages are a valuable source, but time-consuming and costly. The application of reprogramming technologies allows for the generation of macrophages from somatic cells, thereby facilitating the advancement of cell-based therapies for numerous malignant diseases. The composition of CD45+ myeloid-like cell complex (MCC) and induced macrophage (iMac) were analyzed by flow cytometry and single-cell RNA sequencing. The engraftment capacity of CD45+ MCC was evaluated by two transplantation assays. Regulation of c-Myc on MafB was evaluated by ChIP-qPCR and promoter reporter and dual luciferase assays. The phenotype and phagocytosis of iMac were explored by flow cytometry and immunofluorescence. Leukemia, breast cancer, and patient-derived tumor xenograft models were used to explore the anti-tumor function of iMac. Here we report on the establishment of a novel methodology allowing for reprogramming fibroblasts into functional macrophages with phagocytic activity by c-Myc overexpression. Fibroblasts with ectopic expression of c-Myc in iPSC medium rapidly generated CD45+ MCC intermediates with engraftment capacity as well as the repopulation of distinct hematopoietic compartments. MCC intermediates were stably maintained in iPSC medium and continuously generated functional and highly pure iMac just by M-CSF cytokine stimulation. Single-cell transcriptomic analysis of MCC intermediates revealed that c-Myc up-regulated the expression of MafB, a major regulator of macrophage differentiation, to promote macrophage differentiation. Characterization of the iMac activity showed NF-κB signaling activation and a pro-inflammatory phenotype. iMac cells displayed significantly increased in vivo persistence and inhibition of tumor progression in leukemia, breast cancer, and patient-derived tumor xenograft models. Our findings demonstrate that c-Myc alone is enough to reprogram fibroblasts into functional macrophages, supporting that c-Myc reprogramming strategy of fibroblasts can help circumvent long-standing obstacles to gaining “off-the-shelf” macrophages for anti-cancer immunotherapy.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"10 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174609","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}
Unintended pregnancy for female patients with chronic myeloid leukemia (CML) raises the discussion of treatment choices due to the teratogenicity of tyrosine kinase inhibitor (TKI). We report 51 accidental pregnant CML chronic phase (CP) patients with TKI withdrawal immediately after pregnancy from December 2010 to February 2024 to observe the effect of short exposure to TKI on the fetus and the infant outcomes. 59 pregnancies resulted in 100% normal childbirth without birth abnormalities. The median TKI exposure duration was 4 (4–20) weeks in 58 pregnancies, and one pregnancy avoided TKI exposure due to treatment discontinuation of the patient with treatment-free remission (TFR). All newborns had normal birth weight except one premature infant with low birth weight less than the 10th percentile. Up to now, all the children are in good health. 13 (25.5%) and 30 (58.8%) patients had achieved major molecular response (MMR) and deep molecular response (DMR) at pregnancy, respectively. After TKI discontinuation, loss of MMR and complete hematologic response occurred in 6 (46.2%) and 2 (25.0%) patients at delivery, respectively. 38 patients resumed TKI treatment after delivery, and 13 patients without DMR loss sustained TFR after delivery. The median time to regain MMR and DMR were 3 (2–6) months and 6 (1–28) months, respectively. These results demonstrate that TKI discontinuation during pregnancy is feasible for CML-CP patients, and short TKI exposure of pregnant patients has little influence on children’s growth and development.
{"title":"Outcome after short exposure to tyrosine kinase inhibitors in pregnant female patients with chronic myeloid leukemia","authors":"Yingling Zu, Huifang Zhao, Jianling Chen, Huibing Dang, Yanrong Shi, Lixin Liang, Shuhao Mei, Yongping Song, Yanli Zhang","doi":"10.1186/s13045-024-01603-z","DOIUrl":"https://doi.org/10.1186/s13045-024-01603-z","url":null,"abstract":"Unintended pregnancy for female patients with chronic myeloid leukemia (CML) raises the discussion of treatment choices due to the teratogenicity of tyrosine kinase inhibitor (TKI). We report 51 accidental pregnant CML chronic phase (CP) patients with TKI withdrawal immediately after pregnancy from December 2010 to February 2024 to observe the effect of short exposure to TKI on the fetus and the infant outcomes. 59 pregnancies resulted in 100% normal childbirth without birth abnormalities. The median TKI exposure duration was 4 (4–20) weeks in 58 pregnancies, and one pregnancy avoided TKI exposure due to treatment discontinuation of the patient with treatment-free remission (TFR). All newborns had normal birth weight except one premature infant with low birth weight less than the 10th percentile. Up to now, all the children are in good health. 13 (25.5%) and 30 (58.8%) patients had achieved major molecular response (MMR) and deep molecular response (DMR) at pregnancy, respectively. After TKI discontinuation, loss of MMR and complete hematologic response occurred in 6 (46.2%) and 2 (25.0%) patients at delivery, respectively. 38 patients resumed TKI treatment after delivery, and 13 patients without DMR loss sustained TFR after delivery. The median time to regain MMR and DMR were 3 (2–6) months and 6 (1–28) months, respectively. These results demonstrate that TKI discontinuation during pregnancy is feasible for CML-CP patients, and short TKI exposure of pregnant patients has little influence on children’s growth and development.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"16 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166198","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}
Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.
{"title":"Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies.","authors":"Wei-Fang Zuo, Qiwen Pang, Xinyu Zhu, Qian-Qian Yang, Qian Zhao, Gu He, Bo Han, Wei Huang","doi":"10.1186/s13045-024-01601-1","DOIUrl":"10.1186/s13045-024-01601-1","url":null,"abstract":"<p><p>Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The \"Hallmarks of Cancer\" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.</p>","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"17 1","pages":"81"},"PeriodicalIF":29.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11375894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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