Pre-treatment vaccine seroprotection is markedly lower in BCMA-CAR vs CD19-CAR recipients with limited post-therapy modulation

Abstract Introduction:Infections are the leading cause of non-relapse mortality in patients (pts) treated with chimeric antigen receptor T cells (CARs), accounting for more than 50% of all events. This is in part due to prolonged neutropenia, as well as protracted immune reconstitution deficits defined by B-cell aplasia, hypogammaglobulinemia, and sustained CD4+ T-cell lymphopenia. Vaccinations play a fundamental role in the prevention of infectious diseases. A consensus on the optimal post-CAR T-cell vaccination schedule is lacking, as data on the prevalence of protective vaccine titers prior to as well as their persistence after CD19- and BCMA- CAR T treatment remain limited. Aim: We analyzed the antibody titers against common vaccine-preventable infections before and after CD19 and BCMA-directed CART cell therapy. Methods:In this retrospective observational study, we included pts treated with commercial BCMA- or CD19-directed CARs at two German academic centers between 2019 and 2024. Immunoglobulin G (IgG) antibody titers against vaccine-preventable infections (mumps, measles, rubella, varicella zoster virus [VZV], hepatitis [hep] A, hep B and SARS-CoV-2) were assessed prior to CAR T-cell infusion and starting from 3 months after CAR T-cell infusion, according to sample availability. Only pts who had not progressed or received further antineoplastic therapy at timepoint of post-CARs sample collection were considered eligible. Pts treated prior to 01/2021 were excluded from the SARS-CoV-2 analysis.According to institutional guidelines, pts did not receive vaccinations against MMR-V or hepatitis following CAR T cell treatment. However, a substantial percentage of pts underwent SARS-CoV-2 vaccination. Intravenous immunoglobulins (IVIGs) were administered to pts with IgG of < 4 g/L and recurrent infections as per institutional practice. Results: Of the 124 pts included in the analysis, 91 received CD19-directed CARs (Large B-Cell Lymphoma n=77, Mantle Cell Lymphoma n=9, Acute Lymphoblastic Leukemia n=5), while 33 were treated with anti-BMCA CARs (Multiple Myeloma n=32, POEMS n=1). Median age was 63 years (range 19-83). 11/124 pts were administered IVIGs within the 8 weeks prior to titer measurement. Prior to CAR T-cell infusion, the rates of seroprotection were 56% (mumps), 77% (measles), 73% (rubella), 77% (VZV), 48% (hep A), 38% (hep B) and 80% (SARS-CoV-2) across all available pts samples (n=81). Notably, the proportion of seroprotected participants at baseline was significantly higher in lymphoma and leukemia pts compared to myeloma pts for mumps (66.2% vs 0.0%, p<0.0001), measles (88.2% vs 15.4%, p<0.0001), rubella (77.9% vs 46.2%, p=0.036), VZV (88.2% vs 0.0%, p<0.0001) and hep B (42.7% vs 8.3%, p=0.026), while no significant differences were detected concerning hep A (51.5% vs 25.0%) or SARS-CoV-2 (76.7% vs 92.3%). Following CAR T-cell treatment, sample availability amounted to 121 (CD19 n=91, BCMA n=30). Again, we observed significantly higher seroprotection rates in CD19- compared to BCMA-CAR T-cell recipients for mumps (71.4% vs 33.3%, p=0.0004), measles (91.2% vs 60.0%, p=0.0002), rubella (84.6% vs 56.7%, p=0.0043), and VZV (92.3% vs 60.0%, p=0.001). No significant differences were observed for hep A (62.6% vs 82.8%) and B (55.0% vs 65.5%) or SARS-CoV-2 (81.3% vs 92.6%). Paired pre- and post-treatment samples were available for 78 pts (68 CD19, 10 BCMA). Overall, only 1-6% of pts lost immunity after CARs compared to baseline. In a multivariable logistic regression accounting for age, IVIG replacement, CAR T-cell target and baseline seroprotection, seronegativity at baseline was the only factor significantly associated with the absence of immunity after CAR T-cell treatment to hep A, mumps, measles, rubella and VZV, while IVIG replacement showed the strongest association with anti-HBs-positivity. Conclusion: To our knowledge, this is the largest longitudinal study to date assessing vaccine-specific antibody titers in CAR T-cell recipients. We found significantly lower seroprotection rates in BCMA-CAR-T compared to CD19-CAR-T recipients, both at baseline and following therapy. The unexpectedly low antibody titers in multiple myeloma pts may reflect disease-related plasma cell dysfunction and prior treatment, including anti-CD38 antibodies. These real-world findings support the need for tailored vaccination strategies prior and post-CAR-T, with the ultimate goal of reducing infection-related non-relapse mortality.