Donor-Derived CD19-Targeted T Cell Infusion Eliminates B Cell Acute Lymphoblastic Leukemia Minimal Residual Disease with No Response to Donor Lymphocytes after Allogeneic Hematopoietic Stem Cell Transplantation

Leukemia relapse is still the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell acute lymphoblastic leukemia (B-ALL). Relapsed patients with BALL after allo-HSCT have a very short median survival. Minimal residual disease (MRD) is predictive of forthcoming hematological relapse after hematopoietic stem cell transplantation (HSCT);furthermore, eliminating MRD effectively prevents relapse. Donor lymphoblastic infusion (DLI) is the main established approach to treat B-ALL with MRD after allo-HSCT. However, about one-third of patients with MRD are non-responsive to DLI and their prognosis worsens. Although donor-derived cluster of differentiation (CD)19-directed chimeric antigen receptor-modified (CAR) T cells (CART19s) can potentially cure leukemia, the efficiency and safety of infusions with these cells have not yet been investigated in patients with MRD after HSCT. Between September 2014 and February 2018, six patients each received one or more infusions of CART19s from HSCT donors. Five (83.33%) achieved MRD-negative remission, and one case was not responsive to the administration of CAR T cells. Three of the six patients are currently alive without leukemia. No patient developed acute graft-versus-host disease (aGVHD), and no patient died of cytokine release syndrome. Donor-derived CAR T cell infusions seem to be an effective and safe intervention for patients with MRD in B-ALL after allo-HSCT and for those who were not responsive to DLI.

Phase I clinical trial of intracerebral injection of lentiviral-ABCD1 for the treatment of cerebral adrenoleukodystrophy

This was a single-arm,multicenter,open-label phase I trial.Lentiviral vectors(LV)carrying the ABCD1 gene(LV-ABCD1)was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy(CCALD),and multi-site injection was performed.The injection dose increased from 200 to 1600 lL(vector titer:1×10^(9) transduction units per mL(TU/mL)),and the average dose per kilogram body weight ranges from 8 to 63.6 lL/kg.The primary endpoint was safety,dose-exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein.A total of 7 patients participated in this phase I study and were followed for 1 year.No injectionrelated serious adverse event or death occurred.Common adverse events associated with the injection were irritability(71%,5/7)and fever(37.2-38.5℃,57%,4/7).Adverse events were mild and selflimited,or resolved within 3 d of symptomatic treatment.The maximal tolerable dose is 1600 lL.In 5 cases(83.3%,5/6),no lentivirus associated antibodies were detected.The overall survival at 1-year was 100%.The ABCD1 protein expression was detected in neutrophils,monocytes and lymphocytes.This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo;even the maximal dose did not increase the risk of adverse events.Furthermore,the direct LV-ABCD1 injection displayed low immunogenicity.In addition,the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed.This study has been registered in the Chinese Clinical Trial Registry(https://www.chictr.org.cn/,registration number:ChiCTR1900026649).

4SCAR-GD2-modified T-cell therapy in neuroblastoma withamplification: A case report with over 4-year follow-up data

Introduction: Neuroblastoma (NB) is the most common extracranial solid tumor among children. The 5-year event-free survival rate for high-risk (HR) NB is still poor, especially for patients with advanced NB withMYCN gene amplification. Chimeric antigen receptor T (CAR-T) cell therapy is a new treatment for HR-NB.Case presentation: A 55-month-old boy with stage IV HR-NB received 4th-generation CAR-T cells that target disialoganglioside GD2, as consolidation maintenance treatment after intensive chemotherapy, surgery, and autologous stem-cell transplantation. As of February 2019, his CAR-T follow-up time was 37.5 months, indicating prolonged survival. Cranial MRI and ultrasound showed no mass;123I-metaiodobenzylguanidine (123I-MIBG) scan was negative.Conclusion: GD2-CAR-T cells may be an effective treatment option for NB patients withMYCN amplification.