Latent human herpesvirus 6 is reactivated in CAR T cells
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...
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Published in | Nature (London) Vol. 623; no. 7987; pp. 608 - 615 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
16.11.2023
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Subjects | |
Online Access | Get full text |
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Summary: | 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)
. 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
or are in clinical studies
, 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
and may influence the design and production of autologous and allogeneic cell therapies. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions C.A.L. and A.T.S. conceived and designed the study with input from T.P., H.D. and R.G.M. C.A.L. led all analyses. Y.Y., K.M., K.D.S., B.D., T.A., R.R.S., J.M.R., F.A.B. and F.W. carried out experiments and interpreted data. J.C.C., J.C.G., N.J.H., J.M.V., V.L. and A.K. supported the informatics analyses. K.M., J.C.C., L.P., G.G., M.V.M., A.C.T., P.G.T., S.G. and C.J.W. provided data and/or insights related to the in vivo HHV-6 expression. G.Y., J.P., R.S., W.L. and A.S. designed, executed and analysed data related to HHV-6 in vitro CAR T data. A.M., Z.J.R., T.P. and H.D. provided technical review, strategy and guidance for in vitro CAR experiments. A.M.S., L.S.L., T.L.R., M.J.K. and R.G.M. interpreted experiments and impact. C.A.L. and A.T.S. wrote the manuscript with input from all authors. |
ISSN: | 0028-0836 1476-4687 1476-4687 |
DOI: | 10.1038/s41586-023-06704-2 |