Huiwen Jiang

Only 30% to 50% of patients with immune thrombocytopenia (ITP) exhibit a sustained response upon thrombopoietin receptor agonists (TPO-RA) withdrawal, underscoring the necessity for mechanistic elucidation. We enrolled 49 patients treated with TPO-RA for 4 months and performed a follow-up study for 3 months, classifying them into sustained responders (n = 21), and nonsustained responders (n = 28). Compared with total transforming growth factor β1 (TGF-β1) levels, activated TGF-β1 levels (3854 ± 4380 vs 943 ± 1500 pg/mL; P< .001) were significantly elevated in sustained responders, with integrin αvβ8 regulating TGF-β1 activation and restoring immune tolerance. We established a passive ITP model using platelet factor 4–TGF-β1 conditional knockout (CKO) mice, which exhibited a shorter duration of sustained response than wild-type (WT) mice. CKO mice demonstrated a reduced regulatory T-cell (Treg) population, an increased M1-to-M2 macrophage ratio, and more severe megakaryocyte destruction after anti-CD41 injection. Exogenous administration of αvβ8 (250 ng/kg) effectively activated TGF-β1 and prolonged remission after TPO discontinuation in WT mice. Additionally, CD4+ T cells were transfected with lentiviral small interfering RNA or short hairpin RNA to modulate integrin β8 expression and these were injected into severe combined immunodeficiency mice undergoing an active model of ITP. Results showed that β8 overexpression increased Tregs and reduced megakaryocyte damage. Mechanistically, TPO-RA modulated αvβ8-mediated TGF-β1 activation through the activator protein 1family and Smad family member 2 signaling pathways. Furthermore, D-mannose combined with TPO prolonged the response in ITP mice by upregulating αvβ8 and activating TGF-β1. Overall, the integrin αvβ8–mediated activation of TGF-β1 pathway represents a promising therapeutic target for ITP, with substantial potential for clinical application.

Chimeric antigen receptor‐modified T‐cell (CAR‐T) therapy is effective and safe for patients with relapsed/refractory B‐cell acute lymphoblastic leukemia (r/r B‐ALL), but its value has been limited in terms of long‐term leukemia‐free survival. New strategies that can help CAR‐T therapy achieve lasting effect are urgently warranted. This non‐randomized interventional pragmatic clinical trial had a particular aim. It explored whether consolidative allogeneic hematopoietic stem cell transplantation (allo‐HSCT) could improve the long‐term prognosis of the minimal residual disease‐negative complete remission (MRD⁻ CR) patients after CAR‐T therapy. In the first stage, 58 r/r B‐ALL patients received split doses of CAR‐T cells after lymphodepleting chemotherapy, and 51 (87.9%) achieved CR. In the second stage, 21/47 MRD⁻ CR patients without previous allo‐HSCT and contraindications or other restrictions, on their own accord, received consolidative allo‐HSCT within three months after CAR‐T therapy. There was no difference in overall survival (OS) between the MRD⁻ CR patients who received allo‐HSCT and those who did not. However, event‐free survival (EFS) and relapse‐free survival (RFS) were significantly prolonged by allo‐HSCT in the subgroups. This was with either high (≥5%) pre‐infusion bone marrow MRD assessed by flow cytometry (BM‐FCM‐MRD) or poor prognostic markers (P < .05). However, no difference was found in EFS and RFS for patients with pre‐infusion BM‐FCM‐MRD .05). To conclude, CAR‐T therapy bridging to allo‐HSCT is a safe and effective therapeutic strategy for r/r B‐ALL patients, and may prolong their EFS and RFS, especially when they have high pre‐infusion BM‐FCM‐MRD or poor prognostic markers.