Search

BACKGROUND Little is known about pathogen-specific humoral immunity after chimeric antigen receptor–modified T (CAR-T) cell therapy for B cell malignancies. METHODS We conducted a prospective cross-sectional study of CD19-targeted or B cell maturation antigen–targeted (BCMA-targeted) CAR-T cell therapy recipients at least 6 months posttreatment and in remission. We measured pathogen-specific IgG against 12 vaccine-preventable infections and the number of viral and bacterial epitopes to which IgG was detected (“epitope hits”) using a serological profiling assay. The primary outcome was the proportion of participants with IgG levels above a threshold correlated with seroprotection for vaccine-preventable infections. RESULTS We enrolled 65 children and adults a median of 20 months after CD19- (n = 54) or BCMA- (n = 11) CAR-T cell therapy. Among 30 adults without IgG replacement therapy (IGRT) in the prior 16 weeks, 27 (90%) had hypogammaglobulinemia. These individuals had seroprotection to a median of 67% (IQR, 59%–73%) of tested infections. Proportions of participants with seroprotection per pathogen were comparable to population-based studies, but most individuals lacked seroprotection to specific pathogens. Compared with CD19-CAR-T cell recipients, BCMA-CAR-T cell recipients were half as likely to have seroprotection (prevalence ratio, 0.47; 95% CI, 0.18–1.25) and had fewer pathogen-specific epitope hits (mean difference, –90 epitope hits; 95% CI, –157 to –22). CONCLUSION Seroprotection for vaccine-preventable infections in adult CD19-CAR-T cell recipients was comparable to the general population. BCMA-CAR-T cell recipients had fewer pathogen-specific antibodies. Deficits in both groups support the need for vaccine and immunoglobulin replacement therapy studies. FUNDING Swiss National Science Foundation (Early Postdoc Mobility grant P2BSP3_188162), NIH/National Cancer Institute (NIH/NCI) (U01CA247548 and P01CA018029), NIH/NCI Cancer Center Support Grants (P30CA0087-48 and P30CA015704-44), American Society for Transplantation and Cellular Therapy, and Juno Therapeutics/BMS., In this prospective study, we investigated antibodies against vaccine-preventable infections and other pathogen-specific antibodies in individuals with remission after CAR-T cell therapy for B lineage malignancies.

Background Chimeric antigen receptor-modified T (CAR-T) cell immunotherapy for B cell hematologic malignancies results in prolonged B cell depletion. Little is known about the effects of CAR-T cell therapy on pre-existing pathogen-specific humoral immunity. Methods We conducted a prospective, cross-sectional study of children and adults treated with CD19- or BCMA-CAR-T cell therapy. Eligible patients were ≥ 6 months post-CAR-T cell infusion and in remission without subsequent chemoimmunotherapy. We measured total immunoglobulin G (IgG), pathogen-specific IgG levels for 12 vaccine-preventable infections, and B cell subsets from blood. Seroprotective antibody titers were based on standard thresholds. We described the proportion of patients with seroprotective titers and tested for associations between clinical factors and seroprotection using generalized estimating equations. Results We enrolled 65 patients who received CD19- (n=54) or BCMA- (n=11) CAR-T cell therapy. Seven patients were < 18 years old. Samples were collected a median of 20 months (range, 7–68) after CAR T cell infusion. Seroprotection to vaccine-preventable pathogens was generally comparable to the U.S. population (Fig 1) even though blood CD19+ B cell counts were low (< 20 cells/mm3) in 60% of patients. Among 30 patients without IgG replacement in the prior 16 weeks (4 half-lives of IgG), 27 (90%) had hypogammaglobulinemia. Despite this, these individuals had seroprotection to a median of 67% (IQR, 59%-73%) of tested pathogens (Fig 2A). The proportion of patients with seroprotection was lowest for mumps, hepatitis A and B, H. influenzae type B (Hib), S. pneumoniae, and B. pertussis. Patients receiving BCMA-CAR-T cells had seroprotection to fewer pathogens than those receiving CD19-CAR-T cells (Fig 2B), but the difference did not reach statistical significance (Fig 3). There were no significant differences by other variables. Figure 1. Proportion of CAR-T cell recipients with seroprotection to vaccine-preventable infections compared to the U.S. population, stratified by receipt of IgG replacement in the previous 16 weeks. Figure 2 A-B. Percentage of pathogens with seroprotective antibody titers among patients without IgG replacement in the previous 16 weeks. Figure 3. Association of clinical factors with seroprotection to vaccine-preventable infections among patients without IgG replacement in the previous 16 weeks (n=30) Conclusion Seroprotection for vaccine-preventable infections after CD19-CAR-T cell therapy was comparable to the general population. BCMA-CAR-T cell recipients may benefit most from replacement IgG. Vaccinations after CAR-T cell therapy should be considered and prioritized for S. pneumoniae, Hib, hepatitis viruses, and B. pertussis. Disclosures Justin J. Taylor, PhD, Vir Biotechnology (Grant/Research Support) Damian J. Green, MD, Cellectar Biosciences (Grant/Research Support)GSK (Advisor or Review Panel member)Juno Therapeutics (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Royalities)Seattle Genetics (Grant/Research Support, Advisor or Review Panel member) Michael Boeckh, MD PhD, AlloVir (Consultant)EvrysBio (Advisor or Review Panel member, Other Financial or Material Support, share options)Gilead (Consultant, Grant/Research Support)GSK (Consultant)Helocyte (Advisor or Review Panel member, Shareholder)Lophius (Grant/Research Support)Merck (Consultant, Grant/Research Support)SymBio (Consultant)VirBio (Consultant, Grant/Research Support) David G. Maloney, MD, PhD, A2 Biotherapeutics (Consultant, Other Financial or Material Support, Stock Options)Bioline Rx (Consultant)Celgene (Consultant, Grant/Research Support)Gilead (Consultant)Juno Therapeutics (Consultant, Research Grant or Support, Other Financial or Material Support, four pending patents, not issued, licensed, no royalities, no licensees)Kite Pharma (Consultant, Grant/Research Support)Novartis (Consultant)Pharmacyclics (Consultant) Cameron J. Turtle, MBBS, PhD, Allogene (Other Financial or Material Support, Ad hoc advisory board (last 12 months))ArsenalBio (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)AstraZeneca (Grant/Research Support, Other Financial or Material Support, Ad hoc advisory board (last 12 months))Caribou Biosciences (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Century Therapeutics (Advisor or Review Panel member)Eureka Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Juno Therapeutics (Grant/Research Support, Other Financial or Material Support, Patent: Licensed to Juno Therapeutics)Myeloid Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Nektar Therapeutics (Grant/Research Support, Other Financial or Material Support, Ad hoc advisory board (last 12 months))PACT Pharma (Other Financial or Material Support, Ad hoc advisory board (last 12 months))Precision Biosciences (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)TCR2 Therapeutics (Grant/Research Support)T-CURX (Advisor or Review Panel member) Joshua A. Hill, MD, Allogene (Consultant)Allovir (Consultant)Gilead (Consultant)Karius (Grant/Research Support, Scientific Research Study Investigator)Takeda (Grant/Research Support, Scientific Research Study Investigator)