When we get infected with a virus, we typically expect our immune system to work hard to clear all pathogenic particles within a few days. What happens when the immune system isn’t able to get rid of all these microscopic invaders, and instead, the virus hunkers down and hides within our own cells, indefinitely? Certain viruses, such as cytomegalovirus (CMV), are very efficient at just this, having found mechanisms to allow their genome to remain intact within host cells without detection from the immune system for potentially the rest of our lives. No need for serious alarm, though, most people will never even know if they have this little hitchhiker. CMV is highly prevalent in the human population, although remains dormant in as much as 50-80% of us. Occasionally, the dormant, or latent, CMV may try to replicate again, but our immune system tends to do a good job at quelling these events. However, for immunocompromised or immunosuppressed individuals, such as those receiving hematopoietic stem cell or organ transplants, CMV reactivation is a serious concern and can cause significant comorbidities and even mortality.
Chimeric antigen receptor T cell therapy (CARTx) is a relatively new treatment for B-cell and plasma cell-mediated cancers and represents a major breakthrough in treatment for many of these patients. However, it does come with its own side effects, many of which cause immune dysregulation, and as such, these patients often receive immunosuppressive treatments. On top of this, many of these patients already suffer from immunocompromised states due to their underlying disease. As a result, infections are very common and can result in non-relapse mortality in CAR-Tx patients. Studies on CMV reactivation in CARTx patients are severely limited, but could aid in assessing risk to these patients of poor outcomes upon CMV reactivation.
Supported by the Cancer Center Support Grant, this was exactly the question that Dr. Erika Kampouri, from Joshua Hill’s Lab, wanted to address in the recently published article in Clinical Infectious Diseases. Now at the Lausanne University Hospital, Dr. Kampouri highlighted that this was a very important study since limited case studies and retrospective analyses exist. This publication was the first systematic, prospective study of CMV reactivation in CARTx patients. She also noted that these patients are “very uniquely immunocompromised” and currently most treatments and recommendations are “extrapolated from other settings, like the transplant setting”, which is likely underserving CARTx patients.
To carry out this study, the group enrolled 72 CARTx patients who were seropositive for CMV (had previously been infected) and were receiving either CD19, CD20, or BMCA- CARTx for multiple different types of cancers. Collecting blood samples during the first four weeks post treatment was relatively easy as patients remained in the Seattle area, but to continue following these patients after many of them returned home, the research team used a portable blood collection device, which allowed for at home self-collection of blood samples which could then be shipped back to Fred Hutch for testing. Dr. Kampouri highlighted that this was useful during COVID-19 when they wanted to minimize these patients’ exposure to healthcare settings.
From all samples tested, the team found that prior to CARTx therapy, only one patient had detectable CMV reactivation, but post-treatment they were able to detect CMV in as many as 25% of patients within the 12 weeks of their study. As one method for testing how CMV reactivation may be occurring in these patients, they assessed the CMV-cell-mediated immunity (CMV-CMI), and while they found comparable levels to non-immunocompromised controls prior to treatment, there was a significant drop at week 2 that was then recovered by week 4 post-treatment. This observation was certainly interesting, albeit not necessarily surprising, and lends to questions about how CAR-T cells are directly impacting CMV-CMI, noted Dr. Kampouri. When looking for specific risk factors that could indicate which patients were at highest risk for CMV reactivation, they found that the type of CARTx, specifically BMCA-CARTx, and corticosteroid use were associated with twice as much reactivation as other patients. This aligned with what has already been documented but represented the first definitive recognition of these risk factors for CMV reactivation in CARTx patients.
Overall, the data generated from this study was the first of its kind to prospectively study CMV incidence and risk factors in CARTx patients and identified unique subpopulations of patients with highest risk for reactivation. When it comes to how physicians approach CMV reactivation in patients, there has yet to be any clear guidelines set; Dr. Kampouri emphasized that “if you take two centers, there’s a high chance they’re not doing the same thing”. By identifying those with the highest risk, there can now be focused preventative screening and care for patients who may benefit the most. Dr. Kampouri is confident that individualized approaches to care through utilizing all of the tools at their disposal would be the best way forward for supporting CARTx patients, and that CMV monitoring is one of those tools.
This research was funded by the Swiss National Science Foundation and the Cancer Center Support Grant at Fred Hutch.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Jordan Gauthier, David Maloney, Keith Jerome, Wendy Leisenring, Michael Boeckh and Joshua Hill contributed to this work.
Kampouri E, Ibrahimi SS, Xie H, Wong ER, Hecht JB, Sekhon MK, Vo A, Stevens-Ayers TL, Green DJ, Gauthier J, Maloney DG, Perez A, Jerome KR, Leisenring WM, Boeckh MJ, Hill JA. 2023. CMV Reactivation and CMV-Specific Cell-Mediated Immunity after Chimeric Antigen Receptor T-Cell Therapy. Clinical Infectious Diseases. ciad708, https://doi.org/10.1093/cid/ciad708.