lentiglobin gene therapy for transfusion dependent β thalassemia outcomes from the phase 1 2 northstar and phase 3 northstar 2 studies

Introduction Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease characterized by anemia, iron overload and serious comorbidities for which gene therapy may be an effective treatment option. LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with a T87Q substitution. Objective Evaluate the efficacy and safety of LentiGlobin in patients with TDT in the phase 1/2 Northstar (HGB-204; NCT01745120) and phase 3 Northstar-2 (HGB-207; NCT02906202) studies. Methods Patients with TDT (≥100 mL/kg/yr of red blood cells [RBCs] or ≥8 RBC transfusions/yr) received G-CSF and plerixafor for mobilization and HSCs were transduced with the BB305 LVV. Patients underwent single agent busulfan myeloablative conditioning, were infused with transduced cells, and were followed for engraftment, safety, and efficacy. Statistics are presented as median (min – max). Results As of March 7, 2018, 18 patients (12 – 35 yrs) were treated in Northstar (follow-up 32.1 [23.1 – 41.9] months) and as of May 15, 2018, 11 patients (12 – 24 yrs) were treated in Northstar-2 (follow-up 8.5 [0.3 – 16.2] months). Patients received a median cell dose of 8.0 (5.0 – 19.4) CD34+ cells × 106/kg in both studies. The median time to neutrophil and platelet engraftment in both studies was 19 (14 – 30) days and 44 (19 – 191) days, respectively; 1 patient in Northstar-2 (0.3 months follow-up) had not engrafted at time of analysis. Of 6 patients with platelet engraftment ≥ Day 60, 4 had non-serious bleeding events prior to engraftment. All 6 had intact spleens and 3/6 received G-CSF between Days 0 – 21. Both factors appeared associated with time to platelet engraftment. In Northstar, 8/10 patients with non-β0/β0 genotypes and 2/8 patients with β0/β0 genotypes achieved transfusion independence (TI; weighted average hemoglobin [Hb] ≥ 9 g/dL without RBC transfusions for ≥ 12 months). Median Hb during TI was 10.0 (9.3 – 13.1) g/dL. In Northstar-2, 7/8 patients with non-β0/β0 genotypes and ≥ 6 months follow-up stopped RBC transfusions with Hb of 11.1 – 13.3 g/dL at last visit; the first patient treated achieved TI. Non-hematologic grade ≥ 3 adverse events post-infusion in ≥ 5/29 (15%) patients were stomatitis, febrile neutropenia, and pharyngeal inflammation. Veno-occlusive liver disease attributed to busulfan occurred in 4/29 patients (Table 1). There was no transplant-related mortality, vector-mediated replication competent lentivirus, or clonal dominance. Conclusion In Northstar, 80% of patients with non-β0/β0 genotypes achieved TI and early Northstar-2 data suggest that patients can achieve near-normal Hb without transfusions. The safety profile of LentiGlobin is consistent with myeloablative busulfan conditioning. Longer time to platelet engraftment was observed in few patients, but no graft failure or deaths were reported

Betibeglogene Autotemcel Gene Therapy for Non-β⁰/β⁰ Genotype β-Thalassemia

BACKGROUND: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (βA-T87Q) gene. METHODS: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β0/β0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTS: A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONS: Treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-β0/β0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.)

Immune Escape Mechanisms and Future Prospects for Immunotherapy in Neuroblastoma

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood with 5-year survival rate of 40% in high-risk patients despite intensive therapies. Recently, adoptive cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy, represents a revolutionary treatment for hematological malignancies. However, there are challenges for this therapeutic strategy with solid tumors, as a result of the immunosuppressive nature of the tumor microenvironment (TME). Cancer cells have evolved multiple mechanisms to escape immune recognition or to modulate immune cell function. Several subtypes of immune cells that infiltrate tumors can foster tumor development, harbor immunosuppressive activity, and decrease an efficacy of adoptive cell therapies. Therefore, an understanding of the dual role of the immune system under the influences of the TME has been crucial for the development of effective therapeutic strategies against solid cancers. This review aims to depict key immune players and cellular pathways involved in the dynamic interplay between the TME and the immune system and also to address challenges and prospective development of adoptive T cell transfer for neuroblastoma

Strategies to Improve Chimeric Antigen Receptor Therapies for Neuroblastoma

Chimeric antigen receptors (CARs) are among the curative immunotherapeutic approaches that exploit the antigen specificity and cytotoxicity function of potent immune cells against cancers. Neuroblastomas, the most common extracranial pediatric solid tumors with diverse characteristics, could be a promising candidate for using CAR therapies. Several methods harness CAR-modified cells in neuroblastoma to increase therapeutic efficiency, although the assessment has been less successful. Regarding the improvement of CARs, various trials have been launched to overcome insufficient capacity. However, the reasons behind the inadequate response against neuroblastoma of CAR-modified cells are still not well understood. It is essential to update the present state of comprehension of CARs to improve the efficiency of CAR therapies. This review summarizes the crucial features of CARs and their design for neuroblastoma, discusses challenges that impact the outcomes of the immunotherapeutic competence, and focuses on devising strategies currently being investigated to improve the efficacy of CARs for neuroblastoma immunotherapy