Kinetics of Immune Reconstitution after CD19 CAR-T Cell Therapy in ALL Patients

Background: Chimeric antigen receptor (CAR)-T cell therapy has achieved significant efficacy in relapsed or refractory(R/R) hematologic malignancies. CD19 CAR-T cells, which kill B lymphoblasts, but also target normal B lymphocytes, resulting in dysplasia of B cells and suppression of humoral immunity. There were no detailed reports on the profile of immune reconstitution in patients after CD19 CAR-T cell treatment. Our study focused on the kinetics of lymphocyte subsets and immunoglobulin reconstruction in 21 patients with acute lymphoblastic leukemia (ALL) after CD19 CAR-T cell therapy.

Methods: Patients with R/R ALL received CD19 CAR-T cell therapy who obtaining complete response at 1 month after CAR-T cell infusion from April 1, 2016 to Feb 28, 2019 were enrolled (Clinical Trials: NCT02782351). Blood was collected before lymphodepletion therapy and at intervals after CAR-T cell infusion for analysis of complete blood counts, lymphocyte subsets, immunoglobulin, and the amplification of CAR T cells.

Results: We found that the reconstitution of different immune cell subsets occurred at different rates after CD19 CAR-T cell infusion: CD8+ cells were the first to recover, followed by CD16+CD56+ cells and CD3+ cells, and finally CD4+ cells. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell dysplasia occurred in all patients and CD19+ cells returned to normal 79 days after CAR-T cell infusion, which may be related to CAR-T cell depletion. IgG and IgM recovered on day 184 and 242 after CAR-T treatment, respectively. IgA recovered slowly and sustained longer at a low level compared with IgG and IgM, and did not return to normal 1 year after CAR-T cell treatment. A total of 9 infections occurred in 6 (28.57%) patients, including 6 cases with grade 2 infection and 3 cases with grade 3 infection. No patients died of severe infection. In patients with late relapse, IgG, IgA, and IgM were generally normal before CAR-T cell therapy, and were higher than those with early relapse, suggesting that patients with normal immunoglobulin levels before treatment may have longer remission time.

Conclusion: Our results showed the kinetics of lymphocyte subsets and immunoglobulin reconstruction in R/R ALL patients after CD19 CAR-T cell therapy. The recovery of CD8+ cells was fast, whereas the recovery of the CD4+ cell was delayed. All patients developed B cell dysplasia, and it took about 3 months to recover. IgG recovered firstly, followed by IgM and IgA, the later would not recover at least 1 year.