Background: Patients with relapsed or refractory B-cell non-Hodgkin's lymphoma undergoing CD19-targeted CAR T-cell therapy (CAR-T) often develop prolonged B-cell aplasia, leading to impaired humoral immunity and increased infection risk. We previously demonstrated that pneumococcal specific antibody levels are often low prior to CAR-T and decline further afterward (Lee, TCT 2023). Prior studies demonstrated enhanced immune response to pneumococcal conjugate vaccine (PCV13) when administered before and immediately after hematopoietic stem cell transplant (Locke, BMT 2016), but its utility in CAR-T recipients is unknown. We conducted a phase II study to evaluate whether PCV13 vaccination before and after CAR-T can elicit protective immunity against pneumococcus.

Methods: This single-center, phase II study enrolled adults with relapsed/refractory B-cell lymphomas undergoing CD19-targeted CAR-T. Participants received 0.5 mL PCV13 vaccine once between 4 and 21 days before apheresis and again on Days +30 and +90 post-infusion. Primary endpoints were vaccine safety in this setting and humoral seroprotection at day +90, defined as having protective IgG levels [≥1.3 μg/mL] against ≥6 of 11 measured vaccine-specific serotypes. Secondary endpoints included immune reconstitution by flow cytometry, absolute serotype-specific IgG levels, T-cell responses against the vaccine adjuvant, and clinical outcomes. Of 26 enrolled patients, 20 were evaluable for vaccine efficacy, defined as those who received at least one vaccination and had Day +90 immune response data. All patients who received ≥1 vaccine dose comprised the safety population. A Simon two-stage design was used, with continuation to stage II if ≥2 of 10 patients were seroprotected in stage I.

Results: In stage I, 2/10 (20%) patients achieved seroprotection, allowing progression to stage 2 of the study. Enrollment was halted after 26 patients due to discontinuation of PCV13 vaccine. 25 patients received at least protocol related PCV13 vaccine. No vaccine-related serious adverse events were observed in the safety cohort of 25 patients, which included 5 patients not part of the vaccine efficacy cohort: 3 received vaccine but not CAR-T, 1 withdrew consent before day 30, and 1 progressed prior to day 30. Among the 20 evaluable patients for efficacy, 11/20 (55%) were males, the median age was 65 years old (range: 43-83) and the median follow-up period post CAR-T was 15 months (range: 3-51). Diagnoses included diffuse large B cell lymphoma (80%), mantle cell lymphoma (10%) and follicular lymphoma (10%). CAR-T products used were axicabtagene ciloluecel (65%), lisocabtagene maraleucel (20%), brexucabtagene autoleucel (10%) and tisagenlecleucel (5%). Seroprotection rates were low: 10% (2/20) before apheresis, 26% (5/19) on Day -5 pre-CAR-T, then declining to 18% (3/17), 15% (3/20) and 17% (2/12) on Days +30, +90 and +180, respectively. Geometric mean IgG levels against all 11 measured pneumococcal serotypes rose from 0.29 μg/mL pre-apheresis to 0.40 μg/mL at Day -5, then declined over time: 0.31 (Day +30), 0.27 (Day +60), 0.24 (Day +90), and 0.33 μg/mL (Day +180). Mean serum immunoglobulins (IgG, IgA, IgM) pre-apheresis were 706, 105, and 31 mg/dL, respectively. These declined by 3 months (422, 31, and 16 mg/dL) and 6 months (445, 29, and 18 mg/dL). Immune cell counts—including lymphocytes, T cells, B cells, and NK cells—declined, although regulatory T-cell proportions increased over time. Cytokine release syndrome occurred in 18/20 patients (all grade 1–2), with median onset at 2 days post-infusion (range: 1–9). Immune effector cell-associated neurotoxicity syndrome occurred in 65% patients; 15% experienced grade ≥3. No pneumococcal infections occurred during follow up period. At 1 month, 13/20 (65%) patients achieved complete response (CR) and 6/20 (30%) had partial response (PR). By 3 months, 15/20 (75%) had CR, 1/20 (5%) had PR, and 4/20 (20%) had progressive disease. By last follow up, 3/20 (15%) patients died due to lymphoma progression at 7, 15 and 20 months after CAR-T.

Conclusion: PCV13 vaccination before and after CAR-T is safe but provides limited and transient pneumococcal immunity in this immunocompromised population. Ongoing translational work is evaluating if the strategy induced cellular immunity against the CRM adjuvant included in PCV13. These findings support the need to explore alternative strategies like IVIG to enhance protective immunity in CAR-T recipients.

This content is only available as a PDF.
2025
Sign in via your Institution