Latent human herpesvirus 6 is reactivated in chimeric antigen receptor T cells

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 still being understood. For example, we currently lack a comprehensive understanding of the mechanisms of neurotoxicity observed in patients receiving T cell therapies, including recent reports of encephalitis caused by human herpesvirus 6 (HHV-6) reactivation1. Here, via petabase-scale viral RNA data mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in human CD4+ T cells in standard in vitro cultures. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (~1 in 300-10,000 cells) that possess high viral transcriptional activity in chimeric antigen receptor (CAR) T cell culture before spreading to infect other cells in vitro. Through the analysis of single-cell sequencing data from patients receiving cell therapy products that are FDA-approved2 or used in clinical studies3,4, we identify the presence of CAR+, HHV-6 super-expressor T cells in vivo. Together, our study implicates cell therapy products as a source of lytic HHV-6 reported in clinical trials1,5-7 and has broad implications for the design, production, and monitoring of cell therapies.

A new way of identifying viral pathogens reactivating in cellular therapy products

“…The reactivation of HHV‐6B in patients with immunosuppression receiving CAR T‐cell therapy is a potential concern, but we agree with the conclusion of Lareau et al 1 . that this work does not warrant changes to the current standard of care for the management of recipients of autologous products, where routine testing would be of doubtful clinical significance or utility.…”

“…In a recently published article, Lareau et al 1 addressed the important issue of the potential reactivation of viruses in cellular therapy products resulting in disease, especially in view of the recent reports of human herpesvirus 6 (HHV-6) encephalitis in eight recipients of chimeric antigen receptor (CAR) T-cell therapy in three clinical trials. [2][3][4][5] In their study, Lareau et al 1 used the Serratus search engine to identify sequences of 129 viruses from the Sequence Research Archive and matched them for their ability to replicate in human T cells using the ViralZone database. Serratus is a free open-source cloud computing infrastructure.…”

“…In a recently published article, Lareau et al 1 . addressed the important issue of the potential reactivation of viruses in cellular therapy products resulting in disease, especially in view of the recent reports of human herpesvirus 6 (HHV‐6) encephalitis in eight recipients of chimeric antigen receptor (CAR) T‐cell therapy in three clinical trials 2–5 …”

“…In their study, Lareau et al 1 . used the Serratus search engine to identify sequences of 129 viruses from the Sequence Research Archive and matched them for their ability to replicate in human T cells using the ViralZone database.…”

“…Lareau et al 1 . also examined the host cell transcriptomic associations but apart from lymphotoxin alpha found no significant markers for the HHV‐6 highly expressing cells.…”