Antiviral immunity survives CD19-directed therapy

From the Hill and Turtle laboratories, Vaccine and Infections Disease Division and Clinical Research Division

Chimeric antigen receptor T cells (CAR-Ts) are used to treat B cell malignancies by targeting CD19, a surface marker specific for B cells. While CD19 is expressed on malignant B cells, it is also expressed on normal B cells. Therefore, while CD19-directed therapies are effective against disease, treatment often leads to low numbers of normal B cells in patients. B cells provide protection against a variety of pathogens by producing antibodies (or immunoglobulins), a critical component of the immune system. Patients with low B cell numbers (aplasia) often receive prophylactic intravenous immunoglobulins (IVIG) to replace antibodies that protect against pathogens like measles and other viruses. However, IVIG is costly, requires regular infusions, and has not been associated with improved mortality. Dr. Joshua Hill from the Vaccine and Infectious Disease Division and Clinical Research Division wanted to better understand the association of CD19+ B cell aplasia, serum immunoglobulin (IgG) levels, and viral protection in patients following CD19-directed CAR-T therapy. The results of his study were recently published in Blood Advances.

Dr. Hill hypothesized that antibodies against pathogens might remain intact in CD19-CAR-T-treated patients because terminally differentiated B cells, such as long-lived plasma cells (LLPC), have low levels of CD19 and might escape CD19 targeting. LLPC produce large amounts of antibodies and provide a memory response to pathogens previously seen by the immune system. The authors collected data from 39 adult patients with B-cell malignancies with complete remissions for >6 months following CD19 CAR-T cell treatment. Following treatment, 100% of patients (35 tested) had CD19+ B cell depletion within 28 days of treatment. This depletion persisted for a median of 89 days, during which time CAR-T cells were readily detected in the blood. Despite B cell aplasia, the incidence of viral infection remained low, with an incident rate of 0.91 viral infections per person-year, a rate similar to pre-treatment, indicating that risk of viral infection did not increase post-treatment. 

CD19-directed CAR-T cells can recognize and kill malignant cells as well as healthy B cell populations (left). However, plasma cells will low levels of CD19 may escape this targeting and continue to produce antibodies (right) leaving protective immunity intact post CD19 CAR-T therapy.
CD19-directed CAR-T cells can recognize and kill malignant cells as well as healthy B cell populations (left). However, plasma cells will low levels of CD19 may escape this targeting and continue to produce antibodies (right) leaving protective immunity intact post CD19 CAR-T therapy. Provided by Dr. Hill

In order to understand how B cell aplasia might affect antibody levels, total serum IgG levels were measured. An IgG level of <400 mg/dL is the cutoff for a recommendation for IVIG therapy. Prior to CAR-T therapy, 29% of patients had a total IgG level below this cutoff. Post-therapy, 56% of patients had a level below this cutoff. However, when the length of B cell aplasia in each patient was compared to their serum IgG levels over time, there was no evidence that B cell numbers correlated with IgG levels. These data indicated that IgG levels below the IVIG cutoff was common and was seemingly not affected by B cell depletion during treatment. In order to better understand how immunity to specific pathogens was affected, the authors analyzed measles-specific IgG. There was no difference in the average measles IgG concentration in patients pre- or post-therapy, indicating that B cell depletion did not deplete measles protective antibodies. To investigate further, the authors used a new assay called VirScan to evaluate IgG reactivity against multiple viruses that infect humans, as well as the number of unique epitopes within the viruses that antibodies recognized. No significant differences were seen in reactivity to these viruses or the number of epitopes recognized pre- and post-treatment, indicating global viral IgG response remained intact despite CD19+ B cell depletion. One surprising finding was that some patients could recover or develop new antiviral immunity relatively soon after CD19-targeted CAR-T cell therapy based on detection of new or higher levels of virus-specific IgG, further suggesting that viral protection is not dampened by CD19 CAR-T therapy.

While this was a retrospective study, and therefore not designed to determine causal relationships, it challenges the notion that B cell aplasia leads to lower antibody titers and less protection from pathogens. Dr. Hill explained: “This is particularly important because of national shortages of immunoglobulin products like IVIG, as well as their expense and side effects. Although these findings are not enough to change clinical practice, they point to the need to design studies that help us understand whether prophylactic IVIG is beneficial in children and adult recipients of CAR-T cell therapy.” He also mentioned that these results may differ for bacterial pathogens and immunity in children, as they have fewer LLPC, but the study is an important step towards understanding the long-term effects of CD19 CAR-T therapy on immunity. 

This work was supported by funding from the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, the National Heart, Lung, and Blood Institute–funded National Gene Vector Biorepository at Indiana University, and Juno Therapeutics, a Celgene company.

Fred Hutch/UW Cancer Consortium members Joshua Hill, Merav Bar, Stan Riddell, David Maloney, Michael Boeckh, and Cameron Turtle contributed to this work. 

Hill JA, Krantz EM, Hay KA, Dasgupta S, Stevens-Ayers T, Bender Ignacio RA, Bar M, Maalouf J, Cherian S, Chen X, Pepper G, Riddell SR, Maloney DG, Boeckh MJ, Turtle CJ. 2019. Durable preservation of antiviral antibodies after CD19-directed chimeric antigen receptor T-cell immunotherapy. Blood Advances. 3(22):3590-3601.