June 25, 2024

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Reactivation of HHV-6 Virus Found in CAR-T Cells: Implications for Cancer Treatment

Reactivation of HHV-6 Virus Found in CAR-T Cells: Implications for Cancer Treatment

Reactivation of HHV-6 Virus Found in CAR-T Cells: Implications for Cancer Treatment

As a revolutionary cancer therapy, CAR-T cells have transformed the treatment paradigm for hematologic malignancies. However, amid the success of CAR-T cell therapies, scientists are closely monitoring unusual symptoms and clinical outcomes in patients post-treatment.

In the last five years, some patients receiving CAR-T cell therapy have experienced a rare phenomenon: weeks after treatment, patients show initial improvement, only to develop memory loss or, in extreme cases, succumb to death. Surprisingly, the culprit behind these complications is the common human herpesvirus-6 (HHV-6) infection leading to encephalitis.

Under normal circumstances, HHV-6 lies dormant in the human body, coexisting peacefully. The mystery surrounding the origin and implications of HHV-6 in CAR-T cells has troubled scientists.

In a groundbreaking study published in the prestigious journal Nature, a research team led by Caleb A. Lareau from the Memorial Sloan Kettering Cancer Center (MSKCC) and Ansuman T. Satpathy from Stanford University uncovered a subgroup of CAR-T cells with high HHV-6 transcriptional activity, termed “super expressors.” Approximately one in 300 to 10,000 CAR-T cells exhibited this “super expressor” profile.

Crucially, analysis of single-cell sequencing data from patients undergoing FDA-approved or clinical trial CAR-T cell therapy confirmed the presence of HHV-6 “super expressor” CAR-T cells in their bodies. This led the researchers to speculate that reactivated HHV-6 in CAR-T cells might be one source of HHV-6 infection post-CAR-T therapy.

Reactivation of HHV-6 Virus Found in CAR-T Cells: Implications for Cancer Treatment

HHV-6 infection is widespread in the population, with 90% of people experiencing initial infection in infancy, followed by a prolonged dormant period. While primary HHV-6 infection in infancy rarely leads to complications, reactivation in adulthood can result in severe diseases, including encephalitis, especially in immunocompromised individuals.

Reactivation of HHV-6 Virus Found in CAR-T Cells: Implications for Cancer Treatment

Previous studies by the Lareau team hinted at the possibility of HHV-6 reactivation in T cells, and their attention was further piqued by a case report published in the New England Journal of Medicine in 2022. This prompted their investigation into the potential link between HHV-6 reactivation in CAR-T cells and post-treatment encephalitis.

Before delving into CAR-T cell research, the team examined various viruses known for latent replication cycles and reactivation in T cells. HHV-6 emerged as the front-runner, displaying the highest activation levels. Subsequent in vitro cultivation of T cells confirmed HHV-6’s reactivation in T cells.

Further studies involving CAR-T cells from four donors revealed HHV-6 activation during cultivation, with increasing levels of HHV-6 nucleic acid over time. This activation was not uniform across all CAR-T cells but was concentrated in a subset labeled “super expressors.” Approximately 0.01% to 0.3% of cells (1 in 360 to 10,000 cells) exhibited reactivation or high-level expression of HHV-6 transcripts in different patients.

Reactivation of HHV-6 Virus Found in CAR-T Cells: Implications for Cancer Treatment

Proportion of “super expressors”

Notably, after extending T cell amplification to 25 or 27 days, the team observed a significant increase (about 1200-2000 times) in HHV-6 transcript abundance. This increase correlated with 49% and 62% of T cells (including CD4 or CD8 positive) becoming HHV-6 “super expressors,” suggesting active viral replication and spread over time.

Reactivation of HHV-6 Virus Found in CAR-T Cells: Implications for Cancer Treatment

Over time, HHV-6 levels surged

Addressing concerns about the CAR-T cell production process triggering HHV-6 reactivation, the team conducted a 19-day replication of the standard CAR-T cell manufacturing process and found no evidence of HHV-6 activation. They proposed a model where HHV-6 reactivation is a random event influenced by various factors during cell cultivation and intrinsic differences in host cells.

In patient cohorts receiving FDA-approved CAR-T cell therapy, the team observed no HHV-6 activation in CAR-T cells pre-infusion. However, post-infusion CAR-T samples revealed HHV-6 activation. By culturing pre-infusion CAR-T cells for an additional two weeks, the team detected sustained HHV-6 activation between days 5-14.

Based on these findings, they concluded that HHV-6 activation could be detected in vitro or in vivo within 2 to 3 weeks after CAR-T cell product completion. This suggests that the cultivation time of CAR-T cells is crucial for HHV-6 activation, a conclusion supported by longer cultivation times in allogeneic CAR-T cells.

Activation of HHV-6 is time-dependent

Addressing the connection between HHV-6 activation in CAR-T cells and patient complications, the team noted a correlation between the levels of HHV-6 “super expressor” CAR-T cells and changes in patient symptoms. However, this observational result does not establish a causal relationship, requiring further research for confirmation.

In response to the discovery of HHV-6 activation in CAR-T cells, the team investigated methods to suppress this activation. Encouragingly, the antiviral drug foscarnet significantly reduced HHV-6 activation levels without adversely affecting CAR-T cell status. The team emphasized the need for future studies to explore optimal dosages and timing of foscarnet to inhibit HHV-6 activation in CAR-T cells.

Changes in levels of HHV-6 “superexpressers” CAR-T cells coincide with changes in patient symptoms

In summary, Lareau’s team’s research highlights the presence of HHV-6 reactivation in both initial T cells and CAR-T cells. Importantly, HHV-6 reactivation is unrelated to CARs but is influenced by T cell activation, proliferation, and cultivation time. Moreover, active HHV-6 increases over time.

While acknowledging the discovery of HHV-6 reactivation in CAR-T cells, Lareau strongly supports the continued clinical application of CAR-T cells. This revolutionary therapy can save lives, and the treatable nature of HHV-6-induced encephalitis makes it a manageable complication. However, Lareau also suggests that potential virus screening for cell therapy products before infusion could be beneficial in the future. Continuous monitoring throughout the treatment process may further prevent adverse events, improving patient outcomes.

Reactivation of HHV-6 Virus Found in CAR-T Cells: Implications for Cancer Treatment


1.Spanjaart AM, van der Valk FM, van Rooijen G, Brouwer MC, Kersten MJ. Confused about Confusion. N Engl J Med. 2022;386(1):80-87. doi:10.1056/NEJMcps2114818


3.Lareau CA, Yin Y, Maurer K, et al. Latent human herpesvirus 6 is reactivated in CAR T cells. Nature. 2023. doi:10.1038/s41586-023-06704-2

(source:internet, reference only)

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