Cytomegalovirus has an activity shift following CAR T-cell therapy

Our immune system functions like well-equipped soldiers or guards to combat pathogens and for the most part, it does a great job! However, some viruses like herpesviruses have a cunning trick up their sleeve, which is to infect cells and hide in a dormant phase until, for unrelated reasons, the immune system is suppressed. Then, sensing that the guards are away from their post, the virus activates its replicative cycle to make more virus. Cytomegalovirus is a herpesvirus that half of all people encounter before the age of 40, and it’s estimated that about 1 in 3 children in the US become infected with CMV before they turn 5 years old. In immune-competent individuals, CMV infection often goes unnoticed as an asymptomatic infection, and rarely causes CMV mononucleosis. However, in both cases, some CMV-infected cells retain CMV in a dormant state—a phase also known as viral latency—waiting for another opportunity to reactivate and make progeny virus.

There are many ways in which the immune system can be suppressed including the following treatments: chemotherapy, radiation, corticosteroids and others. These regimens are common for patients receiving chimeric antigen receptor (CAR) T-cell therapy, an engineered immune cell-based therapy used for several cancers including blood related cancers like lymphomas, leukemias and myelomas. In these cases of immune suppression during CAR T-cell therapy, how does reactivation of latent CMV impact survival of patients? This is a current question in the field and one that the Group of Dr. Joshua Hill, an Associate Professor in the Vaccine and Infectious Disease and Clinical Research Divisions at Fred Hutch Cancer Center, is equipped to address. In their recent publication in Blood Advances, the Hill Group provides support that CMV reactivation following CAR T-cell therapy is associated with greater patient mortality within the first year after treatment.

Prior to this study, limited information existed about how CMV reactivation impacts recipients of CAR T-cell therapy. “CMV has been linked to indirect effects—such as increased infection risk and higher mortality—in other settings such as in hematopoietic cell and solid organ transplant recipients,” shared first author Dr. Erika Kampouri, a previous medical fellow in the Hill Group and current faculty member in the Clinical Department of Infectious Diseases at Université de Lausanne. These findings spurred the Hill Group to explore the impact of CMV reactivation in CAR T-cell therapy recipients. Dr. Kampouri continued sharing that their approach sought to answer this question by uniquely “using systematic CMV testing and incorporating long-term outcomes” into their analysis. “Our study is among the first to demonstrate an association between CMV reactivation and decreased one-year overall survival after CAR T-therapy,” concluded Dr. Kampouri.

This prospective study was performed using data collected from patients who had known latent CMV infection and received CAR T-cell therapy for one of the following blood related cancers: lymphoma, leukemia, and/or myeloma. Plasma samples were collected prior to chemotherapy treatment to intentionally deplete immune cells and then once a week following CAR T-cell infusion for up to 12 weeks. These patient samples were tested for CMV viremia—the presence of viral particles in the blood—by a PCR-based method. In addition to the chemotherapy regimen, corticosteroid treatment to prolong immune suppression can inadvertently support CMV reactivation. For all 89 patients followed in this study, 25% of these individuals exhibited increased viremia and 9% of patients had “high” viremia benchmarked at greater than or equal to 150 IU/mL. Their analyses found an association that approached statistical significance between detectable CMV viremia, especially high viremia, and poor 1-year overall survival rates. These findings suggest that CMV reactivation negatively impacts survival of these cancer patients receiving CAR T-cell therapy.

“While these findings are important for informing preventive strategies, they are not entirely unexpected—CMV's association with increased mortality is well established in allogeneic HCT, where letermovir prophylaxis [an anti-viral drug] may help mitigate this risk,” explained Dr. Kampouri. “Our study contributes to a limited body of literature on CMV in the context of CAR T-cell therapy, and it fills a critical gap in our knowledge by evaluating CMV's broader impact on long-term outcomes.”

In summary, “our study suggests a potential association between CMV and overall mortality but was not powered to assess the impact on non-relapse mortality,” commented Dr. Kampouri. Future work will use this systematic CMV testing approach to validate these initial findings in a multicenter study with the “aim to uncover the underlying mechanisms—particularly whether CMV reactivation impairs immune reconstitution,” continued Dr. Kampouri. The researchers propose that a multicenter study will support these initial findings and “provide a strong rationale for prophylactic antiviral trials to determine whether preventive strategies can mitigate CMV's indirect effects and improve long-term outcomes after CAR T-cell therapy.” Understanding the impact of CMV reactivation on patient survival following CAR T-cell therapy will inform on best clinical care practices for these patients.  

The spotlighted research was funded by the National Institutes of Health, the Swiss National Science Foundation (SNSF), the Société Industrielle et Commerciale de Produits Alimentaires (SICPA) Foundation, and Merck.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Jordan Gauthier, Mazyar Shadman, Keith Jerome, Wendy Leisenring, Michael Boeckh, Joshua Hill contributed to this work.

Kampouri E, Flaherty PW, Xie H, Sekhon MK, Chalal C, Stevens-Ayers TL, Green DJ, Gauthier J, Shadman M, Pérez-Osorio AC, Jerome KR, Leisenring WM, Boeckh MJ, Hill JA. 2025. The Impact of CMV Reactivation on Mortality After Chimeric Antigen Receptor T-Cell Therapy. Blood Adv. bloodadvances.2024015164. Online ahead of print.