Latent human herpesvirus 6 is reactivated in CAR T cells

Caleb A. Lareau (), Yajie Yin, Katie Maurer, Katalin D. Sandor, Bence Daniel, Garima Yagnik, José Peña, Jeremy Chase Crawford, Anne M. Spanjaart, Jacob C. Gutierrez, Nicholas J. Haradhvala, Janice M. Riberdy, Tsion Abay, Robert R. Stickels, Jeffrey M. Verboon, Vincent Liu, Frank A. Buquicchio, Fangyi Wang, Jackson Southard, Ren Song, Wenjing Li, Aastha Shrestha, Laxmi Parida, Gad Getz, Marcela V. Maus, Shuqiang Li, Alison Moore, Zachary J. Roberts, Leif S. Ludwig, Aimee C. Talleur, Paul G. Thomas, Houman Dehghani, Thomas Pertel, Anshul Kundaje, Stephen Gottschalk, Theodore L. Roth, Marie J. Kersten, Catherine J. Wu, Robbie G. Majzner and Ansuman T. Satpathy ()
Additional contact information
Caleb A. Lareau: Stanford University
Yajie Yin: Stanford University
Katie Maurer: Dana-Farber Cancer Institute
Katalin D. Sandor: Stanford University
Bence Daniel: Stanford University
Garima Yagnik: Allogene Therapeutics
José Peña: Allogene Therapeutics
Jeremy Chase Crawford: St. Jude Children’s Research Hospital
Anne M. Spanjaart: University of Amsterdam
Jacob C. Gutierrez: Stanford University
Nicholas J. Haradhvala: Broad Institute of MIT and Harvard
Janice M. Riberdy: St. Jude Children’s Research Hospital
Tsion Abay: Stanford University
Robert R. Stickels: Stanford University
Jeffrey M. Verboon: Stanford University
Vincent Liu: Stanford University
Frank A. Buquicchio: Stanford University
Fangyi Wang: Stanford University
Jackson Southard: Broad Institute of MIT and Harvard
Ren Song: Allogene Therapeutics
Wenjing Li: Allogene Therapeutics
Aastha Shrestha: Allogene Therapeutics
Laxmi Parida: IBM Research
Gad Getz: Harvard Medical School
Marcela V. Maus: Harvard Medical School
Shuqiang Li: Broad Institute of MIT and Harvard
Alison Moore: Allogene Therapeutics
Zachary J. Roberts: Allogene Therapeutics
Leif S. Ludwig: Berlin Institute of Health at Charité – Universitätsmedizin Berlin
Aimee C. Talleur: Berlin Institute for Medical Systems Biology (BIMSB)
Paul G. Thomas: St. Jude Children’s Research Hospital
Houman Dehghani: Allogene Therapeutics
Thomas Pertel: Allogene Therapeutics
Anshul Kundaje: Stanford University
Stephen Gottschalk: St. Jude Children’s Research Hospital
Theodore L. Roth: Stanford University
Marie J. Kersten: University of Amsterdam
Catherine J. Wu: Dana-Farber Cancer Institute
Robbie G. Majzner: Parker Institute for Cancer Immunotherapy
Ansuman T. Satpathy: Stanford University

Nature, 2023, vol. 623, issue 7987, 608-615

Abstract: Abstract 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 Administration2 or are in clinical studies3–5, 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 trials1,6–8 and may influence the design and production of autologous and allogeneic cell therapies.

Date: 2023
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DOI: 10.1038/s41586-023-06704-2

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