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{"title":"Safety and efficacy of low-dose, cord blood-derived CD19 CAR-NK cells with 4-1BB co-stimulation in refractory systemic lupus erythematosus.","authors":"Zhiru Zeng, Wen Lei, Wenhai Deng, Mo Chen, Weihong Xu, Liang Zhu, Jing Xue, Min Yuan, James Q Wang, Qian Ye, Songzhao Zhang, Qiaohong Wang, Wenbin Qian, Huaxiang Wu","doi":"10.1016/j.medj.2026.101226","DOIUrl":"10.1016/j.medj.2026.101226","url":null,"abstract":"<p><strong>Background: </strong>B cell-targeting chimeric antigen receptor (CAR) T cell therapy has shown efficacy in autoimmune diseases but is limited by toxicity, complex manufacturing, and high cost. Umbilical cord blood (UCB)-derived CAR-natural killer (CAR-NK) cells offer an alternative \"off-the-shelf\" platform with a potentially superior safety profile. We developed a UCB-derived CD19-targeting CAR-NK product incorporating the 4-1BB costimulatory domain (CD19-BBz) and evaluated its safety and efficacy in refractory systemic lupus erythematosus (SLE). This study was registered at ClinicalTrials.gov (ClinicalTrials.gov: NCT06421701).</p><p><strong>Methods: </strong>In this phase 1, open-label, dose-escalation study, five patients with refractory SLE received lymphodepletion chemotherapy followed by infusion of allogeneic CD19-BBz CAR-NK cells. Dosing followed a step-up regimen, with the highest total dose being 1.35 × 10⁹ cells-2.2- to 3.3-fold lower than the highest doses previously reported for CAR-NK therapy in SLE.</p><p><strong>Findings: </strong>Treatment was exceptionally well tolerated. No grade ≥2 cytokine release syndrome and no neurotoxicity or graft-versus-host disease occurred. All patients achieved profound B cell depletion, with nadir circulating B cell levels ranging from 0.16 to 1.44 cells/μL. All patients achieved an SLE Responder Index-4 response by month 1. The lupus low disease activity state was attained in all patients by month 9, and 80% (4/5) met the definition of remission in SLE by the last follow-up (median, 12 months). Reconstituted B cells displayed a sustained naive-dominant repertoire.</p><p><strong>Conclusions: </strong>Low-dose UCB-derived CD19-BBz CAR-NK cell therapy demonstrated an excellent safety profile and induced robust, durable clinical responses in refractory SLE.</p><p><strong>Funding: </strong>This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501300).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101226"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562867","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":"LSD therapy: A few hundred meters from where it began.","authors":"Felix Müller, Anna M Becker, Christopher Böhlke, Matthias E Liechti, Undine E Lang","doi":"10.1016/j.medj.2026.101233","DOIUrl":"10.1016/j.medj.2026.101233","url":null,"abstract":"<p><p>In Basel, only a few hundred meters from where LSD was first synthesized, we tested LSD-assisted therapy for major depression in a randomized trial comparing two high doses with two low doses, each paired with supportive psychotherapy. This Backstory reflects on treating patients, long dosing days, and what remains uncertain.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 8","pages":"101233"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765508","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":"Reprogramming HER2-Positive gastroesophageal cancer immune contexture with bispecific therapy: HERIZON-GEA-01.","authors":"Raghav Sundar, Samuel J Klempner","doi":"10.1016/j.medj.2026.101260","DOIUrl":"10.1016/j.medj.2026.101260","url":null,"abstract":"<p><p>The HERIZON-GEA-01 trial in patients with advanced HER2-positive gastroesophageal adenocarcinoma demonstrated improved outcomes with the addition of the HER2xHER2-bispecific antibody zanidatamab to chemotherapy. The addition of tislelizumab, an anti-PD-1 antibody to chemotherapy and zanidatamab suggests additional survival improvements. HER2-targeting strategies leveraging spatially restricted target degradation and immune modulation are reframing HER2 approaches in HER2-positive gastroesophageal cancer.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 8","pages":"101260"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761850","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":"Tissue-reactive zonation of mesenchymal-like phenotypes in human glioblastoma.","authors":"Alejandro Mossi Albiach, Jokubas Janusauskas, Jesper Kjaer Jacobsen, Ivana Kapustová, Razieh Karamzadeh, Egle Kvedaraite, Lijuan Hu, Marina C M Franck, Maria Ramal García, David Fernández-García, Camiel Mannens, Simone Codeluppi, Johannes B Munting, Lars E Borm, Alia Shamikh, Peter Lönnerberg, Kimberly Siletti, Oscar Persson, Sten Linnarsson","doi":"10.1016/j.medj.2026.101228","DOIUrl":"10.1016/j.medj.2026.101228","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma is the deadliest brain cancer, characterized by large cellular diversity. Both neurodevelopment-like and mesenchymal-like cell states have been described, with the latter being strongly implicated in malignancy and disease progression. However, the spatial organization of these mesenchymal-like cell states has not been systematically described outside the tumor bulk.</p><p><strong>Methods: </strong>We performed deep single-cell RNA sequencing of rare glioblastoma cases where tissue could be sampled from tumor core to macroscopically normal cortex and 888-plex enhanced electric single-molecule fluorescence in situ hybridization (EEL-FISH) spatial transcriptomics on a large cohort of standard resections. We also established four glioblastoma organoid lines to test in vitro inducibility of mesenchymal-like cell states under hypoxia and blood plasma exposure.</p><p><strong>Findings: </strong>We discovered that previously defined mesenchymal-like tumor cell states were shared across both malignant and non-malignant cell types and spatially confined to the tumor bulk. Peripheral regions were instead dominated by neurodevelopment-like tumor states and endogenous microglia. In patient-derived organoids and non-malignant astrocytes, the mesenchymal transcriptional state could be reversibly induced in vitro by hypoxia and human plasma, indicative of a wound response. Multiplex single-molecule spatial transcriptomics revealed that the activation of mesenchymal-like states was associated with hypoxia and organized by distance to perivascular niches.</p><p><strong>Conclusions: </strong>Our findings clarify the cellular landscape and biology of glioblastoma, wherein the mesenchymal state arises at least partly as a reactive tissue state shared by all cells in the tumor bulk.</p><p><strong>Funding: </strong>This work was supported by Region Stockholm, Erling-Persson Family Foundation (Atlas of Childhood Disease), Hjärnfonden (FO2023-0309), Swedish Research Council (2022-01248), and Torsten Söderberg Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101228"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148580381","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":"Immunologic determinants of infusion products and the tumor microenvironment govern response to TIL therapy in advanced melanoma.","authors":"Lilit Karapetyan, Jin Xu, Kimberly Ward, Denise Kalos, Benjamin Schachner, Johannes Ali, Xiaofei Song, Joel Kuriakose, MacLean S Hall, Jamie Chau, Cheryl A Cox, Ayah N Al-Bzour, Rana Falahat, Matthew C Perez, John E Mullinax, Jonathan S Zager, Ricardo Gonzalez, Vernon K Sondak, Kenneth Y Tsai, Jane L Messina, Carlos Moran-Segura, Neale Lopez-Blanco, Anthony E Alleyne, Jonathan V Nguyen, Michael J Schell, Joseph Markowitz, Andrew S Brohl, Zeynep Eroglu, Ahmad A Tarhini, Nikhil I Khushalani, Patrick Hwu, James J Mulé, Amod A Sarnaik, Matthew S Beatty, Shari Pilon-Thomas","doi":"10.1016/j.medj.2026.101231","DOIUrl":"10.1016/j.medj.2026.101231","url":null,"abstract":"<p><strong>Background: </strong>The immunologic features of tumor-infiltrating lymphocyte (TIL) infusion products and their interactions with the tumor microenvironment that govern clinical responses in metastatic melanoma remain incompletely characterized.</p><p><strong>Methods: </strong>We performed integrated immunophenotypic and spatial transcriptomic profiling of TIL infusion products and matched tumor microenvironments from patients treated on early-phase clinical trials.</p><p><strong>Results: </strong>The durable objective response rate was 36%, with a median progression-free survival of 8 months among patients treated with TIL therapy with or without additional therapies. Responders exhibited infusion products enriched for CD8⁺ T cells, stem-like memory subsets, and LAG-3-expressing CD8⁺ T cells, together with enhanced peripheral TIL persistence. The abundance of infused LAG-3+ TILs correlated with tumor reactivity and prolonged progression-free survival. Prior immune checkpoint inhibitor exposure was associated with reduced CD8⁺ stem cell memory T cell frequency and diminished co-stimulatory receptor expression, suggesting impaired TIL fitness. Tumors enriched for tertiary lymphoid structures and spatial immune programs characterized by antigen presentation, interferon signaling, and B cell activation were independently associated with clinical benefit.</p><p><strong>Conclusions: </strong>These findings define an integrated framework linking TIL composition and the tumor microenvironment to therapeutic response and identify potential biomarkers and biological features that may guide patient selection and optimization of TIL therapy.</p><p><strong>Funding: </strong>This work was funded by Iovance Biotherapeutics, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Melanoma Research Alliance, the Donald A. Adam Melanoma & Skin Cancer Center of Excellence, American Cancer Society-Leo and Anne Albert Charitable Foundation Research Scholar Grant, and Melanoma SPORE (P50CA168536).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101231"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13425943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620890","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":"Rewriting the sarcomere: Gene therapy approaches for hypertrophic cardiomyopathy from bench to bedside.","authors":"Susan K Keen, Barry Greenberg, Milind Y Desai","doi":"10.1016/j.medj.2026.101230","DOIUrl":"10.1016/j.medj.2026.101230","url":null,"abstract":"<p><p>Hypertrophic cardiomyopathy (HCM) is a prototypical inherited cardiomyopathy with well-defined sarcomeric genetic underpinnings that make it an attractive target for molecular therapy. We review recent advances in gene-based approaches for HCM, including adeno-associated virus-mediate gene replacement, allele-specific silencing, and emerging gene editing strategies, and highlight the first demonstrations of in vivo target engagement and early clinical translation. Early-phase studies suggest that restoration of sarcomeric biology can favorably impact molecular and structural disease features. We further discuss key challenges related to immune responses, delivery efficiency, response durability, and patient selection that will shape the next phase of development. Together, these developments establish HCM as one of the important early models for cardiac gene therapy and highlight both the promise and complexity of translating genetic insight into durable clinical benefit.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101230"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148621006","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":"Q&A with Michèle Ramsay.","authors":"Michèle Ramsay","doi":"10.1016/j.medj.2026.101220","DOIUrl":"10.1016/j.medj.2026.101220","url":null,"abstract":"<p><p>Michèle Ramsay, PhD, is Director of the Sydney Brenner Institute for Molecular Bioscience, Professor in Human Genetics, and South African Research Chair in Genomics and Bioinformatics of African Populations at the University of the Witwatersrand, Johannesburg. While promoting research excellence in Africa and contributing to research that accurately represents African populations in global science, she supports capacity strengthening in the fields of genomics and precision medicine. Michèle is a founding member of the Human Heredity and Health in Africa Consortium, co-chair of the International Health Cohorts Consortium, member of the WHO Technical Advisory Group for Genomics (TAG-G), and co-chair of the Lancet Commission on Precision Health. She contributes low- and middle-income countries' perspectives to global genomics, promoting ethical, equitable and fair principles and practices.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 8","pages":"101220"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760590","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":"Ethics of gene therapy.","authors":"Julian Savulescu, Sebastian Porsdam Mann, Christopher Gyngell, G Owen Schaefer","doi":"10.1016/j.medj.2026.101225","DOIUrl":"10.1016/j.medj.2026.101225","url":null,"abstract":"<p><p>CRISPR-Cas systems, base editing, and prime editing have made precise genetic interventions possible, and several approved therapies now treat monogenic disorders that were previously untreatable. Heritable genome editing remains ethically contested. We argue that heritable interventions should not be treated as a single category subject to uniform prohibition. We distinguish three targets: catastrophic monogenic disorders, polygenic risk reduction, and non-disease trait enhancement. For catastrophic monogenic conditions in which preimplantation selection cannot yield unaffected embryos, heritable editing is permissible, and the duty of beneficence toward future persons may require it. When the alternative is certain severe suffering or early death, the expected benefits clearly outweigh the risks. For polygenic interventions, current scientific uncertainty makes clinical application premature: predictive validity remains insufficient and pleiotropic effects are poorly understood. For enhancement, the case is weaker still. Some of its benefits are positional; the risks of social stratification are significant; and the evidence base is absent. We conclude that governance frameworks should permit what the evidence supports under stringent safeguards and prohibit what it does not. The central ethical questions concern welfare, not appeals to nature or abstract notions of dignity. Where the evidence warrants it, failing to pursue heritable gene therapy responsibly may itself be an ethical failure. We outline a translational pathway for ethical germline gene editing.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101225"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563222","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":"Spatially defined microenvironmental niches are associated with clinical outcome and tumor ecosystem diversity in head and neck cancer.","authors":"Jianhong An, Erqiang Hu, Qunlun Shen, Jing Zhu, Jiye Zhu, Naijia Liu, Qingxiang Lin, Leti Nunez, Shamsu Bello, Yuting Ren, Selin Kurt, Kelise Harris, Nicole Kawachi, Gregory Rosenblatt, Ruichen Ye, Jeffrey E Segall, Harry Ostrer, Tiffany Hebert, Roger Fecher, Qiang Liu, Mohammed Aminu, Thomas J Ow, Michael B Prystowsky, Amit Verma, Wenjun Deng, Shanye Yin","doi":"10.1016/j.medj.2026.101214","DOIUrl":"10.1016/j.medj.2026.101214","url":null,"abstract":"<p><strong>Background: </strong>Head and neck squamous cell carcinoma (HNSCC) exhibits substantial biological heterogeneity that is not fully explained by human papillomavirus (HPV) status. The spatial organization of tumor, immune, and stromal cell populations and its relationship to clinical outcome remain incompletely understood.</p><p><strong>Methods: </strong>We performed single-cell spatial transcriptomic and proteomic profiling of 44 primary HNSCC tumors, generating a spatial atlas of 19,471,501 cells across whole-slide tissue sections. Spatial niches and ecosystem states were identified through integrated computational analyses and evaluated for associations with tumor programs, clinicopathologic features, and patient outcomes.</p><p><strong>Findings: </strong>HPV-negative tumors were enriched for fibroblast-rich, immune-poor niches associated with epithelial-mesenchymal transition and hypometabolic tumor programs, whereas HPV-positive tumors displayed more diverse immune, stromal, and vascular niche combinations and were enriched for immunogenic ecosystem states. Approximately 20% of HPV-positive tumors exhibited fibroblast-rich ecosystem architectures resembling HPV-negative disease and were associated with less favorable outcomes than other HPV-positive tumors of similar stage. In patient-derived co-culture models, extracellular matrix-associated fibroblasts were associated with epithelial-mesenchymal transition (EMT)-like tumor states, CD8⁺ T cell dysfunction, and chemotherapy resistance-associated phenotypes.</p><p><strong>Conclusions: </strong>Spatial ecosystem architecture is associated with clinically relevant heterogeneity beyond conventional HPV-based classification. Fibroblast-rich, immune-poor ecosystem states characterize a high-risk subset of HPV-positive tumors and may provide a framework for improved biological classification and risk stratification in HNSCC.</p><p><strong>Funding: </strong>This work was supported by the National Institutes of Health (R01CA291607 and R21CA267527-01) and the Feldstein Medical Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101214"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13336309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148377317","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":"Gone but not forgotten: CAR-NK cells leave a lasting mark on autoimmunity.","authors":"Rejeena Shrestha, Rafet Basar","doi":"10.1016/j.medj.2026.101265","DOIUrl":"10.1016/j.medj.2026.101265","url":null,"abstract":"<p><p>In this phase 1 open-label trial, Zeng et al.¹ show that umbilical cord blood-derived CD19 CAR NK-cell therapy is safe and effectively depletes autoreactive B cells in refractory systemic lupus erythematosus (SLE). Despite only transient CAR NK-cell persistence, patients experienced sustained clinical improvement and reconstitution of a predominantly naive B cell compartment, suggesting immune resetting rather than temporary immunosuppression.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 8","pages":"101265"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765454","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}