Patients with B-cell malignancies who achieve durable remissions following treatment with chimeric antigen receptor (CAR) T-cell therapies are at risk of long-term deficiencies in humoral immunity. However, a new study published in JCI Insight has found that seroprotection for vaccine-preventable infections in adults who receive CD19-targeted CAR T-cell therapies is comparable to that observed in the general population. However, those who receive B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies may produce fewer pathogen-specific antibodies, likely placing these individuals at a higher risk of infections.
“These hypothesis-generating findings identify the need for studies of vaccination and immunoglobulin replacement therapy (IGRT) strategies to determine efficacy and identify patients who may benefit most,” the authors, led by Carla Walti, MD, of Fred Hutchinson Cancer Research Center in Seattle, wrote.
This prospective cross-sectional study included 65 children and adults who had received either CD19-targeted (n=54) or BCMA-targeted CAR T-cell therapy (n=11). Patients were enrolled ≥6 months after treatment, and all patients were in remission from an underlying B-lineage malignancy.
Using a serological profiling assay, the investigators measured lymphocyte subsets, immunoglobulins, pathogen-specific IgG for a total of 12 vaccine-preventable infections, and the number of bacterial and viral epitopes to which IgG was detected (“epitope hits”).
Dr. Walti and colleagues sought to identify the proportion of patients who had IgG levels above a threshold associated with seroprotection for the 12 vaccine-preventable infections. These included varicella zoster, polio, rubella, diphtheria, measles, mumps, hepatitis B and C, pertussis, tetanus, influenza, and pneumonia.
Hypogammaglobulinemia, a common occurrence after CAR T-cell therapy, was observed in approximately 90% of the 30 adult patients who did not receive IGRT in the 16 weeks prior to enrollment. The seroprotective IgG titers, however, were detected for a median of 67% of tested pathogens.
The following infections had the lowest proportions of participants with seroprotection:
- mumps (50%)
- hepatitis A virus (43%)
- hepatitis B virus (39%)
- Haemophilus influenzae type b (15%)
- Streptococcus pneumoniae (0%)
- Bordetella pertussis (0%)
The median number of overall epitope hits per participant in those who did not receive IGRT within the preceding 16 weeks was 259, while the median number of viral epitope hits for each participant was 240. The lower number represents a lower degree of antibody diversity.
Overall, the investigators observed that the proportion of individuals with seroprotection per-pathogen in this analysis was comparable to those in population-based studies; however, most patients demonstrated a lack of seroprotection to certain pathogens.
Patients who received BCMA-targeted CAR T-cell therapies were roughly 50% more likely to possess seroprotection to vaccine-preventable infections than those who received CD19-targeted CAR T-cell therapies (prevalence ratio = 0.47; 95% CI 0.18-1.25). Additionally, BCMA-targeted CAR T-cell therapy recipients had fewer pathogen-specific epitope hits (mean difference = –90 epitope hits; 95% CI –157 to –22).
According to the investigators, the lower prevalence of seroprotective antibody titers among BCMA-targeted CAR T-cell therapy recipients relative to CD19-targeted CAR T-cell therapy recipients may be related to depletion of antibody-producing plasma cells. However, both groups largely lacked seroprotective IgG to pathogens known to contribute significantly to morbidity in patients with humoral immunodeficiencies.
“These findings identify the need for studies of vaccination and IGRT strategies to determine efficacy and identify patients who may benefit most.”
—Carla Walti, MD
This study is limited by its relatively short duration. The authors concluded that further longitudinal data are required to understand the direct impact these therapies have on pathogen-specific antibody production.
Based on the findings, the researchers suggest clinicians could optimize the risk-benefit ratio of IGRT by focusing primarily on using the therapy in patients with hypogammaglobulinemia and those who develop severe bacterial infections or have poor responses to immune challenge using an exogenous antigen.
The authors report no relevant conflicts of interest.
Walti CS, Krantz EM, Maalouf J, et al. Antibodies against vaccine-preventable infections after CAR-T cell therapy for B cell malignancies. JCI Insight. 2021;6(11):146743.