B-cell maturation antigen (BCMA) or CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy can lead to profound B-cell aplasia and associated hypogammaglobulinemia, and on-target, off-tumor, toxicity.1–5 This immunocompromised state can persist beyond one year and contribute to increased morbidity after CAR-T therapy.3 It is uncertain if vaccine-induced IgG antibodies against pathogens persist after CAR-T therapy. Several reports of patients treated with CD19-targeted CAR-T therapy demonstrated preservation of specific IgG antibodies.6,7 In contrast, there is concern for more compromised pathogen-specific humoral immunity following BCMA–CAR-T therapy due to on-target depletion of antibody-producing plasma cells.4 In this study, Dr. Carla S. Walti and colleagues evaluated humoral immunity against vaccine-specific pathogens after either CD19- or BCMA-directed CAR-T therapy.
This prospective cross-sectional observational study in pediatric and adult patients treated with CD19- or BCMA-targeted CAR-T therapy assessed humoral immunity against 12 standard vaccine-preventable infections (HAV, HBV, varicella zoster virus, measles, mumps, rubella, Haemophilus influenzae [Hib], Clostridium tetani, Corynebacterium diphtheriae, Bordetella pertussis, Streptococcus pneumoniae, and poliovirus). Patients were eligible if alive and in remission for more than six months after CAR T-cell infusion without additional antitumor therapy. Sixty-five patients, with a median follow-up of 20 months from CAR-T infusion, were identified. Vaccine-specific IgG antibody concentration and number of viral and bacterial epitopes detected by the IgG antibodies (“epitope hits”) were measured at any time point at least six months post– CAR-T therapy.
The analysis focused primarily on a subset of 30 patients who had not received immunoglobulin replacement therapy (IGRT) within 16 weeks prior to data collection (26 CD19 CAR-T recipients and 4 BCMA CAR-T recipients). Ninety percent had a total IgG level below the lower limit of normal (< 610 mg/dL). Among these patients, the proportion with seroprotective IgG titers was comparable to U.S. population-based studies, with the exception of B pertussis (0%; 95% CI, 0%-22%) and S pneumoniae (0%; 95% CI, 0%-13%). There was a lower prevalence of patients with seroprotective IgG (prevalence ratio, 0.47; 95% CI, 0.18-1.25) and number of viral and bacterial epitopes detected by IgG antibodies (mean difference, –90 epitope hits; 95% CI, –157-–22) among the four BCMA CAR-T recipients than the 26 CD19 CAR-T recipients. On univariable analysis, BCMA CAR target and interval less than one year from CAR-T infusion were negatively associated with seroprotective antibody titers, though the difference did not meet significance. BCMA CAR target, history of hematopoietic stem cell transplantation, and CD19+ B-cells greater than 20 cells/μL were significantly negatively associated with epitope hits.
The investigators analyzed B-cell phenotype in 23 patients with peripheral blood B-cells of at least 20 cells/μL and found that naïve and transitional B cells were the predominant phenotype with rare, switched memory cells. In those same 23 patients, B cells specific for respiratory syncytial virus, as a representative pathogen, were also found to be a predominately naïve B-cell phenotype. This pattern was similar in both CD19 and BCMA CAR-T recipients.
In Brief
This study provides important data describing antibodies and B-cell phenotype after CAR-T therapy, pertinent to a patient population without guidelines as to the utility and timing of vaccination or revaccination. Additional data and consensus are urgently needed, particularly given the COVID-19 pandemic. The study demonstrated that patients at a median of 20 months after CAR-T therapy have vaccine-specific seroprotective IgG titers against standard vaccine-specific pathogens similar to the U.S. population. However, interpretation is limited due to the cross-sectional observational nature of this study. Even though the study focused on CAR-T recipients who did not receive IGRT, the study did not report if patients received any of the vaccines after CAR-T infusion, other than exclusion of one patient who received vaccines against seven pathogens. Whether or not there is lower prevalence of seroprotection in the small number of BCMA CAR-T recipients is unclear. Patients with multiple myeloma develop severe humoral immune suppression secondary to disease and standard therapies,8 and are already at tenfold and sevenfold higher risk for viral and bacterial infections, respectively.9 The study also highlighted lack of humoral immunity against S pneumoniae in CAR-T recipients. This is concerning as S pneumoniae is one of the most common encapsulated organisms that can lead to significant morbidity in patients with humoral immunodeficiency.10 Finally, the prevalence of naïve B cells after CAR-T highlight the need to re-establish a memory B-cell pool in CAR-T recipients.
It remains unknown if vaccination immediately prior to CAR-T therapy could prime CD19-negative plasma cells to generate vaccine-specific antibodies after the therapy, if patients have T cells responsive against vaccine peptides or adjuvants, or whether patients can mount a vaccinespecific response prior to B-cell recovery. Well-designed observational and interventional studies are needed to better actively protect CAR-T patients against infections.
Competing Interests
Dr. Lee indicated no relevant conflicts of interest. Dr. Locke acts as a scientific advisor and his institution receives research funding from Kite Pharma, Novartis, and BMS, each of which has U.S. Food and Drug Administration–approved CAR-T therapies.
