Chimeric antigen receptor (CAR) T cell therapies have transformed care for various types of blood cancers. These therapies are incredibly effective, often yielding complete remission even when used to treat cases of refractory or relapsed malignancies.
Most currently approved CAR-T cell therapies do not specifically target cancerous cells, but rather the entire class of cells that contains the malignancy. They target either B cells – that patrol the body for invading pathogens and initiate adaptive immune responses – or plasma cells – that produce antibodies that block and eliminate pathogens. Patients with B cell cancers like non-Hodgkin Lymphoma and lymphocytic leukemia receive CAR-T cell therapies that recognize and kill cells expressing B cell-specific surface proteins CD19 and CD20. Patients with plasma cell cancers like multiple myeloma receive CAR-T cell therapies directed to plasma cells with the cell surface B cell maturation antigen (BCMA) protein. While these therapies effectively eliminate cancerous cells, they also target and deplete healthy, non-cancerous B cells or plasma cells in most recipients. It remains unclear how this depletion of healthy cells impacts immunity.
Researchers in Dr. Joshua Hill’s group in the Vaccine and Infectious Disease and Clinical Research Divisions investigated the consequences of B cell lineage CAR-T therapies for immune protection and response in a recent study published in Nature Communications. "Our study tackles a key question in the CAR-T field: what happens to long-term immune protection after these therapies? While CAR-T is remarkably effective at treating cancer, it also disrupts the B cell and plasma cell populations that normally maintain immunity after prior infections and vaccines,” said Dr. Stosh Ozog, the leading author of the publication.
In the prospective study run at Fred Hutch Cancer Center and Seattle Children’s Hospital, the team followed 128 participants – 100 receiving CD19 or CD20 targeted CAR-T therapy and 28 receiving BCMA targeted therapy – from a pre-CAR-T timepoint through 6 months to 1 year after treatment. They assessed immune cell counts and antibody levels to a variety of vaccine-preventable pathogens over time. As expected, participants who underwent CD19 or CD20-directed CAR T therapy had a significant decrease in B cells. Participants in both groups had a decrease in plasma cells.
CAR-T therapy was not associated with significant changes in antibody levels. Dr. Ozog commented, “We found that most patients retain stable antibody levels overall through therapy, but many still lack protective immunity to a meaningful number of vaccine-preventable infections coming into therapy.” Participants who received BCMA-targeted therapies had especially low levels of protective antibodies across all timepoints, likely a consequence of their plasma cell malignancies.
Encouragingly, the team found that vaccination after CAR-T therapy boosts pathogen-specific antibody levels in a substantial proportion of participants, especially among BCMA CAR-T recipients. There was a significant association between CD19 B cell levels and the development of protective antibodies with vaccination. It seems that patients with plasma cell malignancies lose protective immunity with their disease but retain the B cells necessary for effective vaccine responses after CAR-T therapy. Patients with B cell malignancies retain more pre-existing antibody immunity, but lose B cells, and therefore the ability to robustly respond to vaccination, from B cell targeted CAR-T therapy. The study results, however, suggests that this loss of B cells is temporary – 39% of recipients had recovery of B cells to pre-CAR-T levels by 1 year after treatment.
Dr. Ozog indicated, “This work is already starting to shape how we think about vaccination strategies for CAR-T recipients here at Fred Hutch, and we hope it helps inform approaches to protecting this rapidly growing patient population more broadly.”
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Drs. Jordan Gauthier, Brian Till, Mazyar Shadman, Marie Bleakley, Michael Boeckh, and Joshua Hill contributed to this research.
The spotlighted research was funded by the National Institutes of Health.
Ozog S, Krantz EM, Tindbaek K, Munoz J, Liu WL, Chalal C, Pernikoff S, Yahya K, Stevens-Ayers T, Dasgupta S, Cowan AJ, Green DJ, Gauthier J, Till BG, Gardner RA, Shadman M, Bleakley M, Boeckh M, Boonyaratanakornkit J, Turtle CJ, Hill JA. 2026. Influence of B cell-lineage targeted CAR-T cell therapy on humoral immunity and vaccine-induced antibody response. Nature Communications. doi: 10.1038/s41467-026-71473-1
Science Spotlight writer Ashley Person is a PhD candidate in the Cohn lab in the Vaccine and Infectious Disease Division at Fred Hutch. She studies how HIV-infected cells persist over time in people living with HIV on long term treatment.