Hrishikesh K Srinagesh, Anne Marijn Kramer, John H Baird, Agnes Reschke, Bita Sahaf, Juancarlos Cancilla, Shriya Syal, Yi-Jiun Su, Neha Agarwal, Alexandria M Jensen, Liora M Schultz, Nikeshan Jeyakumar, Sneha Ramakrishna, Kara L Davis, Saurabh Dahiya, Steven A Feldman, Crystal L Mackall, Lori S Muffly, David B Miklos, Matthew J Frank
{"title":"Clinical and Cytokine Features of Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome.","authors":"Hrishikesh K Srinagesh, Anne Marijn Kramer, John H Baird, Agnes Reschke, Bita Sahaf, Juancarlos Cancilla, Shriya Syal, Yi-Jiun Su, Neha Agarwal, Alexandria M Jensen, Liora M Schultz, Nikeshan Jeyakumar, Sneha Ramakrishna, Kara L Davis, Saurabh Dahiya, Steven A Feldman, Crystal L Mackall, Lori S Muffly, David B Miklos, Matthew J Frank","doi":"10.1158/2643-3230.BCD-25-0262","DOIUrl":"10.1158/2643-3230.BCD-25-0262","url":null,"abstract":"<p><p>Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a poorly characterized inflammatory toxicity of chimeric antigen receptor (CAR) T cells with high risk of mortality. In this study, we describe IEC-HS manifestations in patients with large B-cell lymphoma and B-cell acute lymphoblastic leukemia after CD22-directed CAR T cells. IEC-HS occurred in 19 of 54 patients (35%), including 11 grade 1 and 8 grade 2 or higher. IEC-HS was associated with higher nonrelapse mortality (NRM) yet lower relapse rates. CAR T-cell expansion in peripheral blood was significantly associated with IEC-HS severity. Cytokine profiling identified 41 cytokines primarily related to the IFNγ, TNFα, and IL1 families that significantly correlated with IEC-HS severity. We developed a parsimonious model composed of IFNγ, IL10, and IL1RA that correlated with grade 2+ IEC-HS on day 14, outperforming the full signature (AUC 0.93 vs. 0.75, P = 0.038). Thus, a cytokine signature with potential prognostic utility helps distinguish IEC-HS from inflammatory toxicities with overlapping symptoms.</p><p><strong>Significance: </strong>IEC-HS is a serious inflammatory toxicity of CAR T cells. We demonstrate that IEC-HS after CD22-directed CAR T-cell therapy is associated with lower rates of relapse yet higher NRM. CAR T-cell expansion and a 41-cytokine signature are associated with IEC-HS, and a simplified signature of IFNγ, IL10, and IL1RA precedes severe disease. See related commentary by Rocco and Shah, p. 163.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"225-233"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12834480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Seeing Is Believing: IEC-HS after CAR T Cells.","authors":"Joseph M Rocco, Nirali N Shah","doi":"10.1158/2643-3230.BCD-25-0463","DOIUrl":"10.1158/2643-3230.BCD-25-0463","url":null,"abstract":"<p><p>Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a complication seen in patients receiving chimeric antigen receptor (CAR) T cells, more frequently in those with CD22- or BCMA-targeted constructs compared with CD19. While associated with higher CAR T-cell expansion and a unique cytokine profile, the constellation of three cytokines (IFNγ, IL10, and IL1RA) correlated most strongly with IEC-HS severity and may help guide preemptive interventions. See related article by Srinagesh et al., p. 225.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"163-165"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"First-line Therapy in Newly Diagnosed Multiple Myeloma.","authors":"Kevin C Miller, Saad Z Usmani","doi":"10.1158/2643-3230.BCD-25-0384","DOIUrl":"10.1158/2643-3230.BCD-25-0384","url":null,"abstract":"<p><p>First-line multiple myeloma treatment has evolved from melphalan-prednisone to quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation, yielding significantly improved survival. This review summarizes current approaches to risk stratification and therapy for newly diagnosed multiple myeloma and highlights the emerging role of measurable residual disease-adaptive strategies. We also discuss recent efforts to integrate chimeric antigen receptor T cells and bispecific antibodies into up-front treatment. As biology-driven strategies advance, select patients may achieve durable treatment-free remissions. Ongoing studies will clarify how to best tailor therapy while balancing efficacy, toxicity, and survivorship toward functional cures.</p><p><strong>Significance: </strong>Despite unprecedented advances, multiple myeloma therapy remains largely uniform and emphasizes indefinite treatment. Herein, although summarizing current standard-of-care therapy, we advocate for individualized approaches informed by disease biology, treatment response, and emerging biomarkers. Novel strategies incorporating immunotherapies are paving the way toward treatment-free remissions and functional cures in select patients.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"195-211"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hector Huerga Encabo, Giuseppe D'Agostino, Katherine Sturgess, Alice E Lord, Eric D Jong, Alessandra Ferrelli, Aneesh Sharma, Syed A Mian, Khadidja Habel, Miriam Llorian-Sopena, Amirtha Priya Ramesh, Fatihah Mohamad Nor, Helene Foissner, Manuel Garcia-Albornoz, Lynette Graver, Despoina Papazoglou, Steven Ngo, Fernando Anjos-Afonso, Linda Ariza-McNaughton, Gabriella Ficz, Dominique Bonnet
{"title":"Human TET2-Mutant Clonal Hematopoiesis Expansion Is Driven by Distinct Inflammatory Signaling Responses in Stem Cells Versus Myeloid Progeny.","authors":"Hector Huerga Encabo, Giuseppe D'Agostino, Katherine Sturgess, Alice E Lord, Eric D Jong, Alessandra Ferrelli, Aneesh Sharma, Syed A Mian, Khadidja Habel, Miriam Llorian-Sopena, Amirtha Priya Ramesh, Fatihah Mohamad Nor, Helene Foissner, Manuel Garcia-Albornoz, Lynette Graver, Despoina Papazoglou, Steven Ngo, Fernando Anjos-Afonso, Linda Ariza-McNaughton, Gabriella Ficz, Dominique Bonnet","doi":"10.1158/2643-3230.BCD-25-0070","DOIUrl":"10.1158/2643-3230.BCD-25-0070","url":null,"abstract":"<p><p>Clonal hematopoiesis (CH) increases with age and is associated with severe outcome in the course of infections or tumor development. Understanding the environmental conditions that favor mutant clones and the CH immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. Using human cells, we unravel a cell-specific and opposite impact of TET2 mutations on hematopoietic stem and progenitor cells (HSPC) compared with their myeloid progeny. Multi-omic analyses reveal that TET2-mutant HSPCs exhibit intrinsic epigenetic silencing of AP-1 transcription factors and a blunted transcriptional adaptation to systemic inflammation. Conversely, monocyte-macrophage trajectory derived from TET2Mut hematopoietic stem cells (HSC) contributes to exacerbated inflammation. Together, these findings reconcile how TET2-mutant CH can simultaneously promote increased stemness within the HSPC compartment and heightened inflammation through its myeloid progeny, providing mechanistic insight into how TET2-CH expands under inflammatory stress.</p><p><strong>Significance: </strong>This study reveals that stress conditions inducing emergency myelopoiesis expand human TET2-mutant clones. TET2 mutation triggers an epigenetic silencing of AP-1 factors contributing to the dampening of the inflammatory responsiveness in TET2mut HSPCs while simultaneously promoting hyperinflammatory TET2mut monocyte-macrophage activation and differentiation, reinforcing inflammation.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"287-305"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7618546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145670120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anjana Anilkumar Sithara, Veronika Kapustova, David Zihala, Ondrej Venglar, Daniel Bilek, Moutaz Helal, Mara John, Eva Radova, Lucie Broskevicova, Jan Vrana, Gabriela Havlova, Ludmila Muronova, Tereza Popkova, Jana Mihalyova, Hana Plonkova, Serafim Nenarokov, Kamlesh Bisht, Hongfang Wang, Helgi Van de Velde, Sandra Charvatova, Ivo Demel, Michal Kascak, Milan Navratil, Martin Havel, Juli Bago, Michal Simicek, Angela Riedel, Leo Rasche, Tereza Sevcikova, Ola Landgren, Roman Hajek, Tomas Jelinek
{"title":"Composition and Functional State of T and NK Cells in the Extramedullary Myeloma Tumor Microenvironment.","authors":"Anjana Anilkumar Sithara, Veronika Kapustova, David Zihala, Ondrej Venglar, Daniel Bilek, Moutaz Helal, Mara John, Eva Radova, Lucie Broskevicova, Jan Vrana, Gabriela Havlova, Ludmila Muronova, Tereza Popkova, Jana Mihalyova, Hana Plonkova, Serafim Nenarokov, Kamlesh Bisht, Hongfang Wang, Helgi Van de Velde, Sandra Charvatova, Ivo Demel, Michal Kascak, Milan Navratil, Martin Havel, Juli Bago, Michal Simicek, Angela Riedel, Leo Rasche, Tereza Sevcikova, Ola Landgren, Roman Hajek, Tomas Jelinek","doi":"10.1158/2643-3230.BCD-25-0170","DOIUrl":"10.1158/2643-3230.BCD-25-0170","url":null,"abstract":"<p><p>Extramedullary multiple myeloma (EMM) is a high-risk feature of multiple myeloma associated with increased resistance to treatments, including modern immunotherapies, and shorter survival. The composition and functional state of immune cells within the EMM tumor microenvironment (TME) remain poorly understood. Using single-cell RNA sequencing, flow cytometry, and spatial transcriptomics, we revealed significant differences in the EMM TME compared with multiple myeloma bone marrow (BM). T and NK cells were verified as the most abundant immune subsets in the EMM TME. Compared with the BM counterparts, we found these tumors to have a significantly reduced effector-to-tumor cell ratio, a significantly lower number of CD4+ T cells, and an increased proportion of regulatory CD16- NK cells. We observed a high proportion of exhausted, tumor-reactive CD8+ T cells in roughly half of EMM tumors. Furthermore, we identified elevated expression of immune checkpoints, such as PD-1 on CD8+ T cells and KLRC1 (NKG2A) on CD16- NK cells.</p><p><strong>Significance: </strong>This study characterizes the TME in EMM lesions and paired BM from patients with multiple myeloma, revealing a high proportion of less cytotoxic CD16- NK cells in EMM tumors and suggesting that direct cell-cell interactions may underlie the CD8+ T-cell exhaustion observed in a subset of these tumors.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"250-265"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13012251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Annamaria Gullà, Madhav V Dhodapkar, Hermann Einsele, Marc S Raab, Antonio G Solimando, Cirino Botta, Marcello Turi, Lilli S Sester, Andrew J Portuguese, Torsten Steinbrunn, Kenneth C Anderson
{"title":"Rethinking Multiple Myeloma Treatment: The Biological and Clinical Insights Guiding Immune-Based Combinations.","authors":"Annamaria Gullà, Madhav V Dhodapkar, Hermann Einsele, Marc S Raab, Antonio G Solimando, Cirino Botta, Marcello Turi, Lilli S Sester, Andrew J Portuguese, Torsten Steinbrunn, Kenneth C Anderson","doi":"10.1158/2643-3230.BCD-25-0107","DOIUrl":"10.1158/2643-3230.BCD-25-0107","url":null,"abstract":"<p><p>The standard of care for multiple myeloma has rapidly evolved to include immune-based therapies. However, achieving durable immune control and long-term survival, particularly in high-risk patients, remains difficult. In this article, we review the immune effects of existing and emerging therapies, dissect key drivers of resistance, highlight rational combinations and treatment-sequencing strategies, and summarize ongoing clinical trials that aim to optimize durable immune control. We discuss how the application of these biological and clinical insights may help us rethink multiple myeloma treatment to fully eradicate residual disease and elicit sustained natural and/or synthetic tumor-specific immunity.</p><p><strong>Significance: </strong>Preclinical and clinical insights are reshaping how immune-based therapies are used in multiple myeloma. This review explores how optimizing the integration of natural and synthetic immunity can support a shift from disease control to deep, durable immune eradication, paving the way for personalized immune strategies tailored to individual immune profiles.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"176-194"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charlotte Syrykh, Sarah Bertoli, Jean-Marc Alliot, Pierre Brousset
{"title":"Expectations and Limitations of Artificial Intelligence in Blood Cancer Diagnosis.","authors":"Charlotte Syrykh, Sarah Bertoli, Jean-Marc Alliot, Pierre Brousset","doi":"10.1158/2643-3230.BCD-25-0443","DOIUrl":"10.1158/2643-3230.BCD-25-0443","url":null,"abstract":"<p><p>In this commentary, we open the debate on what can be expected from artificial intelligence (AI) in the diagnosis of hematologic cancers. We discuss the key factors that make AI solutions robust, trustworthy, and, above all, generalizable, with particular emphasis on the importance of dataset quality in shaping the performance and effectiveness of AI models.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"171-175"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A Triumvirate of Transformation: Oncogene, Ontogeny, and Plasticity.","authors":"Bisi Miao, Jian Xu","doi":"10.1158/2643-3230.BCD-26-0006","DOIUrl":"10.1158/2643-3230.BCD-26-0006","url":null,"abstract":"<p><p>Cancer cells display extensive heterogeneity that influences therapy response and clinical outcome, yet the underlying mechanisms remain incompletely understood. Recent studies reveal that the developmental state and molecular plasticity of target cells, together with genetic lesions, drive cellular transformation, disease heterogeneity, and treatment response in hematologic malignancies. See related article by Hartmann et al., p. 306 (9) See related article by Wang et al. (8).</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"168-170"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Haley Newman, Shawn H R Lee, Petri Pölönen, Rawan Shraim, Yimei Li, Hongyan Liu, Richard Aplenc, Shovik Bandyopadhyay, Changya Chen, Meenakshi Devidas, Caroline Diorio, Kimberly Dunsmore, Omar Elghawy, Amira Elhachimi, Tori Fuller, Sumit Gupta, Junior Hall, Andrew D Hughes, Stephen P Hunger, Mignon L Loh, Zachary Martinez, Michael F McCoy, Cassidy G Mullen, Stanley B Pounds, Elizabeth Raetz, Anna Eames Seffernick, Gongping Shi, Jonathan Sussman, Kai Tan, Lahari Uppuluri, Tiffaney L Vincent, Ruth Wang'ondu, Lena E Winestone, Stuart S Winter, Brent L Wood, Gang Wu, Jason Xu, Wenjian Yang, Charles G Mullighan, Jun J Yang, Kira Bona, David T Teachey
{"title":"Correction: Impact of Genetic Ancestry on Genomics and Survival Outcomes in T-cell Acute Lymphoblastic Leukemia.","authors":"Haley Newman, Shawn H R Lee, Petri Pölönen, Rawan Shraim, Yimei Li, Hongyan Liu, Richard Aplenc, Shovik Bandyopadhyay, Changya Chen, Meenakshi Devidas, Caroline Diorio, Kimberly Dunsmore, Omar Elghawy, Amira Elhachimi, Tori Fuller, Sumit Gupta, Junior Hall, Andrew D Hughes, Stephen P Hunger, Mignon L Loh, Zachary Martinez, Michael F McCoy, Cassidy G Mullen, Stanley B Pounds, Elizabeth Raetz, Anna Eames Seffernick, Gongping Shi, Jonathan Sussman, Kai Tan, Lahari Uppuluri, Tiffaney L Vincent, Ruth Wang'ondu, Lena E Winestone, Stuart S Winter, Brent L Wood, Gang Wu, Jason Xu, Wenjian Yang, Charles G Mullighan, Jun J Yang, Kira Bona, David T Teachey","doi":"10.1158/2643-3230.BCD-25-0464","DOIUrl":"10.1158/2643-3230.BCD-25-0464","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"331"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paul Lin, Sunil Acharya, Francia Reyes-Silva, Rafet Basar, Nadima Uprety, Luz Yurany Moreno Rueda, Pei Lin, April L Gilbert, Pinaki P Banerjee, Dexing Fang, Chenyu Zhang, Ana Karen Nunez Cortes, Luciana Melo Garcia, May Daher, Luis Muniz-Feliciano, Gary M Deyter, Vernikka Woods, Seema Rawal, Ping Li, Corry M Jones, Rejeena Shrestha, Muzaffar H Qazilbash, Krina K Patel, Hans C Lee, Richard E Champlin, David Marin, Elizabeth J Shpall, Robert Z Orlowski, Katayoun Rezvani
{"title":"CD70-Targeting CAR NK Cells Overcome BCMA Downregulation and Improve Survival in High-risk Multiple Myeloma Models.","authors":"Paul Lin, Sunil Acharya, Francia Reyes-Silva, Rafet Basar, Nadima Uprety, Luz Yurany Moreno Rueda, Pei Lin, April L Gilbert, Pinaki P Banerjee, Dexing Fang, Chenyu Zhang, Ana Karen Nunez Cortes, Luciana Melo Garcia, May Daher, Luis Muniz-Feliciano, Gary M Deyter, Vernikka Woods, Seema Rawal, Ping Li, Corry M Jones, Rejeena Shrestha, Muzaffar H Qazilbash, Krina K Patel, Hans C Lee, Richard E Champlin, David Marin, Elizabeth J Shpall, Robert Z Orlowski, Katayoun Rezvani","doi":"10.1158/2643-3230.BCD-25-0130","DOIUrl":"10.1158/2643-3230.BCD-25-0130","url":null,"abstract":"<p><p>CD70 is highly expressed in many cancers, including multiple myeloma. We show in two cohorts of patients with multiple myeloma that CD70 is elevated in several high-risk disease categories and correlates with poor survival. These findings were validated using single-cell RNA sequencing, flow cytometry, and IHC. Moreover, we demonstrate the feasibility of targeting CD70 in myeloma using NK cells engineered with a chimeric antigen receptor (CAR) incorporating the CD70 cognate receptor CD27 and IL-15 (CAR27/IL-15). CAR27/IL-15 NK cells exerted potent in vitro and in vivo cytotoxicity against CD70+ multiple myeloma cells, comparable with CAR27/IL-15 T cells, and remained effective in BCMA knockout models. Collectively, these results establish CD70 as a promising therapeutic target for high-risk multiple myeloma, particularly for patients who relapse after BCMA-directed therapy, providing preclinical support for the ongoing phase I/II clinical trial of CD70-targeting CAR NK cells (NCT05092451).</p><p><strong>Significance: </strong>We demonstrate that CD70 expression is elevated in patients with high-risk multiple myeloma and in patients with t(4;14) translocation. CD70-targeting CAR NK cells exhibit potent cytotoxicity against CD70+ multiple myeloma cells and significantly improve survival in xenograft mouse models of multiple myeloma, even in the absence of BCMA expression. See related commentary by Benson Jr and Caligiuri, p. 166.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"234-249"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13012245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145379117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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