Immunologic effects of rituximab on the human spleen in immune thrombocytopenia

221

160

• CD19-targeted T-cell immunotherapy reveals that a population of PCs lacking CD19 expression survives long-term, independent of B cells.• Preexisting humoral immunity to vaccine-related antigens can persist in patients despite marked B-cell aplasia after CTL019 immunotherapy.The mechanisms underlying the maintenance of long-lasting humoral immunity are not well understood. Studies in mice indicate that plasma cells (PCs) can survive up to a lifetime, even in the absence of regeneration by B cells, implying the presence of longlived PCs as a mechanism for long-lasting immunity. Evidence from humans treated with anti-CD20, which depletes circulating B cells, also suggests B-cell-independent longterm survival of some PCs. On the other hand, antibody responses may be sustained solely by short-lived PCs with repopulation from clonally related memory B cells. To explore PC longevity and humoral immunity in humans, we investigated the fate of PCs and their antibodies in adult and pediatric patients who received chimeric antigen receptor-based adoptive T-cell immunotherapy targeting CD19 to treat B-cell lineage malignancies (CTL019). Treatment with CTL019 is frequently associated with B-cell aplasia that can persist for years. Serum antibody titers to vaccine-related antigens were measured, and quantitative assessment of B cells and PCs in blood and bone marrow was performed at various time points before and after CTL019 therapy. While total serum immunoglobulin concentrations decline following CTL019-induced B-cell aplasia, several vaccine/pathogen-specific serum immunoglobulin G and A (IgG and IgA) titers remain relatively stable for at least 6 and 12 months posttreatment, respectively. Analysis of bone marrow biopsies after CTL019 revealed 8 patients with persistence of antibody-secreting PCs at least 25 months post-CTL019 infusion despite absence of CD19 1 CD20 1 B cells. These results provide strong evidence for the existence of memory B-cell-independent, long-lived PCs in humans that contribute to long-lasting humoral immunity. (Blood. 2016;128(3):360-370)

Section: Discussionmentioning

confidence: 99%

Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

Bhoj

Arhontoulis

Wertheim

et al. 2016

221

160

“…41 However, Audia et al reported different results that RTX showed no effect on Tregs in ITP. 43 More clinical trials with large sample sizes are required to further investigate the sustained response of the combination of RTX and rhTPO.…”

Section: Discussionmentioning

confidence: 99%

A multicenter randomized open-label study of rituximab plus rhTPO vs rituximab in corticosteroid-resistant or relapsed ITP

Zhou

Qin

et al. 2015

Key Points• Rituximab plus recombinant human thrombopoietin is superior to rituximab monotherapy for corticosteroid-resistant or relapsed ITP patients.This study aimed to compare the efficacy and safety of rituximab (RTX) plus recombinant human thrombopoietin (rhTPO) with RTX alone in patients with immune thrombocytopenia (ITP) who had failed to respond to corticosteroids or relapsed. Recruited patients were randomized at a ratio of 2:1 into 2 groups: the combination group (RTX 1 rhTPO, n 5 77) and the monotherapy group (RTX, n 5 38). Overall response was achieved in 79.2% of patients in the combination group vs 71.1% in the monotherapy group (P 5 .36), and the complete response (CR) rate was 45.4% in the combination group compared with 23.7% in the monotherapy group (P 5 .026). The combination group had significantly shorter time to response (TTR; median and range, 7 and 4-28 days) compared with the monotherapy group (28 and 4-90 days) (P < .01). There was no difference between these 2 groups in terms of the long-term response (P 5 .12). Our findings demonstrated that the combination of RTX and rhTPO significantly increased the CR rate and shortened TTR compared with RTX monotherapy in the treatment of corticosteroid-resistant or relapsed ITP but failed to show a beneficial effect on the long-lasting response. This study is registered at www.clinicaltrials.gov as #NCT01525836. (Blood. 2015;125(10):1541-1547

“…8 Previous studies have indicated that regulatory T cells (Treg) are deficient, both in the blood and the spleen of ITP patients. 12,13 More recently, a decrease in circulating CD19 1 CD24 hi CD38 hi B cells and in the overall production of interleukin 10 (IL-10) by B cells has also been reported, consistent with a regulatory B-cell deficiency.…”

Section: Introductionmentioning

confidence: 88%

“…12 On the other hand, we have shown that failure to respond to RTX was associated with the persistence of splenic plasma cells producing anti-platelet antibodies 29 and to an imbalance between effector and regulatory T cells in the spleens of ITP patients who do not respond to RTX, consistent with an increase in the Th1/Treg ratio. 13 We thus hypothesized that such an imbalance may foster CD8…”

Section: Introductionmentioning

confidence: 99%

Preferential splenic CD8+ T-cell activation in rituximab-nonresponder patients with immune thrombocytopenia

Audia

Samson

Mahévas³

et al. 2013

Self Cite

• Activated CD81 T cells are preferentially found in the spleen of ITP patients who are nonresponders to rituximab.The pathogenic role of B cells in immune thrombocytopenia (ITP) has justified the therapeutic use of anti-CD20 antibodies such as rituximab (RTX). However, 60% of ITP patients do not respond to RTX. To decipher the mechanisms implicated in the failure of RTX, and because the spleen plays a well-recognized role in ITP pathogenesis, 12 spleens from ITP patients who had been nonresponders to RTX therapy were compared with 11 spleens from RTX-untreated ITP patients and 9 controls. We here demonstrate that in RTX-nonresponder ITP patients, preferential Th1 and Tc1 T lymphocyte polarizations occur, associated with an increase in splenic effector memory CD8 1 T-cell frequency. Moreover, in the RTX-nonresponder patient group, the CD8 1 T-cell repertoire displays a restricted pattern. In the blood, the phenotype of CD8 1T cells before and after RTX treatment is not modified in responders or nonresponders. Altogether, these results demonstrate for the first time an activation of splenic CD8 1 T cells in ITP patients who did not respond to RTX and suggest their involvement in platelet destruction in these patients. (Blood. 2013;122(14):2477-2486