PMID- 37938768 OWN - NLM STAT- MEDLINE DCOM- 20231130 LR - 20240503 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 623 IP - 7987 DP - 2023 Nov TI - Latent human herpesvirus 6 is reactivated in CAR T cells. PG - 608-615 LID - 10.1038/s41586-023-06704-2 [doi] AB - Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)(1). Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4(+) T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration(2) or are in clinical studies(3-5), we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials(1,6-8) and may influence the design and production of autologous and allogeneic cell therapies. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Lareau, Caleb A AU - Lareau CA AUID- ORCID: 0000-0003-4179-4807 AD - Department of Pathology, Stanford University, Stanford, CA, USA. lareauc@mskcc.org. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. lareauc@mskcc.org. AD - Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. lareauc@mskcc.org. AD - Department of Genetics, Stanford University, Stanford, CA, USA. lareauc@mskcc.org. AD - Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. lareauc@mskcc.org. FAU - Yin, Yajie AU - Yin Y AUID- ORCID: 0000-0002-2220-005X AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. FAU - Maurer, Katie AU - Maurer K AUID- ORCID: 0000-0002-4160-181X AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. AD - Harvard Medical School, Boston, MA, USA. AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - Sandor, Katalin D AU - Sandor KD AUID- ORCID: 0000-0003-2892-4865 AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. FAU - Daniel, Bence AU - Daniel B AUID- ORCID: 0000-0002-2410-8767 AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. FAU - Yagnik, Garima AU - Yagnik G AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Pena, Jose AU - Pena J AUID- ORCID: 0000-0002-9662-906X AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Crawford, Jeremy Chase AU - Crawford JC AUID- ORCID: 0000-0003-4096-6048 AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Spanjaart, Anne M AU - Spanjaart AM AUID- ORCID: 0000-0003-0167-6021 AD - Department of Hematology, University of Amsterdam, Amsterdam, the Netherlands. FAU - Gutierrez, Jacob C AU - Gutierrez JC AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. FAU - Haradhvala, Nicholas J AU - Haradhvala NJ AUID- ORCID: 0000-0003-1113-3135 AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - Riberdy, Janice M AU - Riberdy JM AD - Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Abay, Tsion AU - Abay T AUID- ORCID: 0009-0009-0024-2732 AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. FAU - Stickels, Robert R AU - Stickels RR AUID- ORCID: 0000-0003-4326-4084 AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. FAU - Verboon, Jeffrey M AU - Verboon JM AD - Department of Pathology, Stanford University, Stanford, CA, USA. FAU - Liu, Vincent AU - Liu V AUID- ORCID: 0000-0002-6790-6603 AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. AD - Department of Genetics, Stanford University, Stanford, CA, USA. FAU - Buquicchio, Frank A AU - Buquicchio FA AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. FAU - Wang, Fangyi AU - Wang F AUID- ORCID: 0009-0000-8310-3088 AD - Department of Pathology, Stanford University, Stanford, CA, USA. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. FAU - Southard, Jackson AU - Southard J AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. FAU - Song, Ren AU - Song R AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Li, Wenjing AU - Li W AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Shrestha, Aastha AU - Shrestha A AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Parida, Laxmi AU - Parida L AUID- ORCID: 0000-0002-7872-5074 AD - IBM Research, New York, NY, USA. FAU - Getz, Gad AU - Getz G AUID- ORCID: 0000-0002-0936-0753 AD - Harvard Medical School, Boston, MA, USA. AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Cancer Center, Massachusetts General Hospital, Boston, MA, USA. FAU - Maus, Marcela V AU - Maus MV AUID- ORCID: 0000-0002-7578-0393 AD - Harvard Medical School, Boston, MA, USA. AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Cancer Center, Massachusetts General Hospital, Boston, MA, USA. FAU - Li, Shuqiang AU - Li S AUID- ORCID: 0000-0001-9106-6141 AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. AD - Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. FAU - Moore, Alison AU - Moore A AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Roberts, Zachary J AU - Roberts ZJ AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Ludwig, Leif S AU - Ludwig LS AD - Berlin Institute of Health at Charite - Universitatsmedizin Berlin, Berlin, Germany. AD - Max-Delbruck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. FAU - Talleur, Aimee C AU - Talleur AC AUID- ORCID: 0000-0002-6558-6706 AD - Max-Delbruck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. FAU - Thomas, Paul G AU - Thomas PG AUID- ORCID: 0000-0001-7955-0256 AD - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Dehghani, Houman AU - Dehghani H AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Pertel, Thomas AU - Pertel T AD - Allogene Therapeutics, South San Francisco, CA, USA. FAU - Kundaje, Anshul AU - Kundaje A AUID- ORCID: 0000-0003-3084-2287 AD - Department of Genetics, Stanford University, Stanford, CA, USA. AD - Department of Computer Science, Stanford University, Stanford, CA, USA. FAU - Gottschalk, Stephen AU - Gottschalk S AUID- ORCID: 0000-0003-3991-7468 AD - Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Roth, Theodore L AU - Roth TL AUID- ORCID: 0000-0002-3970-9573 AD - Department of Pathology, Stanford University, Stanford, CA, USA. FAU - Kersten, Marie J AU - Kersten MJ AUID- ORCID: 0000-0002-8904-3802 AD - Department of Hematology, University of Amsterdam, Amsterdam, the Netherlands. FAU - Wu, Catherine J AU - Wu CJ AUID- ORCID: 0000-0002-3348-5054 AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. AD - Harvard Medical School, Boston, MA, USA. AD - Broad Institute of MIT and Harvard, Cambridge, MA, USA. FAU - Majzner, Robbie G AU - Majzner RG AUID- ORCID: 0000-0001-6969-8011 AD - Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. AD - Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA. AD - Division of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA. FAU - Satpathy, Ansuman T AU - Satpathy AT AUID- ORCID: 0000-0002-5167-537X AD - Department of Pathology, Stanford University, Stanford, CA, USA. satpathy@stanford.edu. AD - Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. satpathy@stanford.edu. AD - Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. satpathy@stanford.edu. LA - eng GR - K99 HG012579/HG/NHGRI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R50 CA251956/CA/NCI NIH HHS/United States GR - UM1 HG012076/HG/NHGRI NIH HHS/United States PT - Journal Article DEP - 20231108 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Receptors, Chimeric Antigen) SB - IM MH - Humans MH - *CD4-Positive T-Lymphocytes/immunology/virology MH - Clinical Trials as Topic MH - Gene Expression Regulation, Viral MH - Genomics MH - *Herpesvirus 6, Human/genetics/isolation & purification/physiology MH - *Immunotherapy, Adoptive/adverse effects/methods MH - Infectious Encephalitis/complications/virology MH - *Receptors, Chimeric Antigen/immunology MH - Roseolovirus Infections/complications/virology MH - Single-Cell Gene Expression Analysis MH - Viral Load MH - *Virus Activation MH - *Virus Latency PMC - PMC10999258 MID - NIHMS1979850 COIS- Competing interests A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. C.A.L. and L.S.L. are consultants to Cartography Biosciences. N.J.H. is a consultant for Constellation Pharmaceuticals. C.J.W. holds equity in BioNTech Inc and receives research funding from Pharmacyclics. G.G. receives research funds from IBM and Pharmacyclics, and is a founder of, consultant for and holder of private equity in Scorpion Therapeutics. M.V.M. is an inventor on patents related to CAR T cell therapies held by the University of Pennsylvania (some licensed to Novartis), holds equity in TCR2, Century Therapeutics, Genocea, Oncternal and Neximmune, has served as a consultant for multiple companies involved in cell therapies, receives research support from KitePharma and Moderna, and serves on the Board of Directors of 2Seventy Bio. M.J.K. has received research funding from Kite, a Gilead Company, as well as honoraria from Kite, a Gilead Company, Novartis, Takeda, Miltenyi Biotec, BMS/Celgene, Beigene and Adicet Bio. S.G. is a co-inventor on patent applications in the fields of cell or gene therapy for cancer, a consultant for TESSA Therapeutics and a member of the Data and Safety Monitoring Board of Immatics, and has received honoraria from Tidal, Catamaran Bio, Sanofi and Novartis within the past 2 years. J.C.C. and P.G.T. are named on patent applications in the fields of T cell or gene therapy for cancer. G.Y., J.P., R.S., W.L., A.S., A.M., Z.J.R., T.P. and H.D. are employees and shareholders of Allogene Therapeutics. A.K. is a scientific cofounder of Ravel Biotechnology Inc., is on the scientific advisory board of PatchBio Inc., SerImmune Inc., AINovo Inc., TensorBio Inc. and OpenTargets, is a consultant with Illumina Inc. and owns shares in DeepGenomics Inc., Immunai Inc. and Freenome Inc. R.G.M. is a cofounder of and holds equity in Link Cell Therapies and CARGO Therapeutics, and is a consultant for Lyell Immunopharma, NKarta, Arovella Pharmaceuticals, Innervate Radiopharmaceuticals, Aptorum Group, Gadeta, FATE Therapeutics (Data and Safety Monitoring Board) and Waypoint Bio. All other authors declare no competing interests. EDAT- 2023/11/08 12:42 MHDA- 2023/11/27 12:44 PMCR- 2024/04/07 CRDT- 2023/11/08 11:59 PHST- 2022/08/12 00:00 [received] PHST- 2023/10/03 00:00 [accepted] PHST- 2023/11/27 12:44 [medline] PHST- 2023/11/08 12:42 [pubmed] PHST- 2023/11/08 11:59 [entrez] PHST- 2024/04/07 00:00 [pmc-release] AID - 10.1038/s41586-023-06704-2 [pii] AID - 10.1038/s41586-023-06704-2 [doi] PST - ppublish SO - Nature. 2023 Nov;623(7987):608-615. doi: 10.1038/s41586-023-06704-2. Epub 2023 Nov 8.