Meeting FDA Guidance recommendations for replication-competent virus and insertional oncogenesis testing

Cornetta, Kenneth; Lin, Tsai-Yu; Pellin, Danilo; Kohn, Donald B.

doi:10.1016/j.omtm.2022.11.009

Cited by 16 publications

(6 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In normal, especially post-transplantation hematopoiesis, clonal dominance was thought to be an uncommon but potential occurrence and an important outcome of malignant progression 26 . The vector-related adverse events include insertional mutagenesis and replication competent lentiviruses (RCL) 27 . Integration site analysis (ISA), which has been a necessary bioinformatic method recommended by FDA, was applied to monitor the insertional oncogenesis.…”

Section: Methodsmentioning

confidence: 99%

Gene therapy using optimized LentiHBB^T87Qvector in two patients with transfusion dependent β-thalassemia

Han

Ouyang

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: Gene therapy is gradually becoming recognized as a possibly curative therapeutic strategy for transfusion-dependent β-thalassemia (TDT). Gene therapy addresses the problem of donor scarcity through the application of autologous hematopoietic stem cells (HSCs), which also can reduce the risks that accompany allogeneic HSC transplantation. When using gene addition strategy, lentiviral vector is critical for the efficacy and safety of β-thalassemia gene therapy. In our preclinical studies, LentiHBBT87Qvector with optimized backbone was developed to efficiently restore β-globin expression in HSCs-derived erythroblasts of TDT patients with minimal risk of tumorigenesis. Here, we presented the clinical trial results of gene therapy using LentiHBBT87Qvector in two TDT patients. Method: In an ongoing phase 1/2 trial (NCT05745532), auto-HSCs were mobilized from two TDT patients, and then transduced with LentiHBBT87Qvector. The gene-modified auto-HSCs is called HGI-001 injection. After four-day consecutive myeloablative conditioning, these two patients were administrated with HGI-001 injection via intravenous infusion. Medical examinations were performed in the transplantation unit to monitor patients' status till the patients were clinically stable. Then, 24-month following-up visits are conducted to assess the safety and efficacy of HGI-001 injection. The safety endpoints of this clinical study include the incident and severity of adverse events (AEs); transplant-related mortality or disability events within 100 days post drug product infusion; vector-related replication competent lentivirus (RCL) and clonal variations containing specific viral integration sites; overall survival during this clinical trial. The major efficacy endpoint is the percentage of subjects with average vector copy number (VCN) in peripheral blood mononuclear cells (PBMCs) >0.1, and average expression of exogenous HbAT87Q>2.0g/dL at the 24th month after reinfusion of HGI-001 injection Results: The rapid neutrophil and platelet engraftment successfully happened after reinfusion of HGI-001 injection. The two patients with non-β0/β0genotype have been transfusion-independent for 24 months and 21 months post-treatment. At the last visit, the levels of HbAT87Qare 7.3 and 6.9g/dL, and the levels of total hemoglobin are 9.8 and 10.1 g/dL. After the two subjects stopped transfusions, the iron overload has been alleviated without iron chelation treatment. Most AEs are myeloablative conditioning related, and can be controlled through clinically standard therapeutic managements. No clone dominance related to vector integration nor RCL has been observed. Conclusion: Gene therapy with optimized LentiHBBT87Qvector (HGI-001 injection) assist two TDT patients become transfusion-independent without serious adverse events related to the product.

show abstract

Section: Methodsmentioning

confidence: 99%

Gene therapy using optimized LentiHBB^T87Qvector in two patients with transfusion dependent β-thalassemia

Han

Ouyang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…First, despite the development of increasingly safe reporter vectors, there is a risk of inser-tional mutagenesis [41]. Fortunately, no cases have been reported of tumor transformation of CAR T cells obtained via transduction and introduced into a patient [42,43]. However, there is evidence that CAR T cell clones with a certain integration locus can gain a selective advantage [44].…”

Section: Comparison Of Viral Transduction and Crispr/cas Technology F...mentioning

confidence: 99%

Increasing Gene Editing Efficiency via CRISPR/Cas9- or Cas12a-Mediated Knock-In in Primary Human T Cells

Kruglova,

Shepelev

2024

Biomedicines

View full text Add to dashboard Cite

T lymphocytes represent a promising target for genome editing. They are primarily modified to recognize and kill tumor cells or to withstand HIV infection. In most studies, T cell genome editing is performed using the CRISPR/Cas technology. Although this technology is easily programmable and widely accessible, its efficiency of T cell genome editing was initially low. Several crucial improvements were made in the components of the CRISPR/Cas technology and their delivery methods, as well as in the culturing conditions of T cells, before a reasonable editing level suitable for clinical applications was achieved. In this review, we summarize and describe the aforementioned parameters that affect human T cell editing efficiency using the CRISPR/Cas technology, with a special focus on gene knock-in.

show abstract

“…The FDA had added requirements for cell product release measurements, including demonstration of the absence of replication‐competent lentivirus in each patient's Drug Product, despite this having never been reported to occur with the LV systems in clinical use for over a decade. The National Gene Vector Biorepository, supported by the National Heart Lung and Blood Institute offered a series of essential assays to support gene therapy at academic centers and had an available RCL assay that we were able to use to evaluate the cell products to be used 45 …”

Section: Efs‐ada Gene Therapy Returned To Academiamentioning

confidence: 99%

“…The National Gene Vector Biorepository, supported by the National Heart Lung and Blood Institute offered a series of essential assays to support gene therapy at academic centers and had an available RCL assay that we were able to use to evaluate the cell products to be used. 45 The FDA also required measurement of vector copy number in the portion of cells that had been transduced (VC/transduced cell) and not just the bulk population average. We had developed an assay to measure VC/transduced cell by growing progenitor colony-forming units (CFU) from the Drug Product in methylcellulose and performing droplet digital PCR on 30-40 colonies and reporting the average VCN from all PCR+ CFU.…”

Section: Lentivir Al Vec Tor S (Lv )mentioning

confidence: 99%

Gene therapy for adenosine deaminase severe combined immune deficiency—An unexpected journey of four decades

Kohn

2023

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

SummarySevere combined immune deficiency due to adenosine deaminase deficiency (ADA SCID) is an inborn error of immunity with pan‐lymphopenia, due to accumulated cytotoxic adenine metabolites. ADA SCID has been treated using gene therapy with a normal human ADA gene added to autologous hematopoietic stem cells (HSC) for over 30 years. Iterative improvements in vector design, HSC processing methods, and clinical HSC transplant procedures have led nearly all ADA SCID gene therapy patients to achieve consistently beneficial immune restoration with stable engraftment of ADA gene‐corrected HSC over the duration of observation (as long as 20 years). One gene therapy for ADA SCID is approved by the European Medicines Agency (EMA) in the European Union (EU) and another is being advanced to licensure in the U.S. and U.K. Despite the clear‐cut benefits and safety of this curative gene and cell therapy, it remains challenging to achieve sustained availability and access, especially for rare disorders like ADA SCID.

show abstract

Meeting FDA Guidance recommendations for replication-competent virus and insertional oncogenesis testing

Cited by 16 publications

References 57 publications

Gene therapy using optimized LentiHBB^T87Qvector in two patients with transfusion dependent β-thalassemia

Gene therapy using optimized LentiHBB^T87Qvector in two patients with transfusion dependent β-thalassemia

Increasing Gene Editing Efficiency via CRISPR/Cas9- or Cas12a-Mediated Knock-In in Primary Human T Cells

Gene therapy for adenosine deaminase severe combined immune deficiency—An unexpected journey of four decades

Contact Info

Product

Resources

About

Meeting FDA Guidance recommendations for replication-competent virus and insertional oncogenesis testing

Cited by 16 publications

References 57 publications

Gene therapy using optimized LentiHBBT87Qvector in two patients with transfusion dependent β-thalassemia

Gene therapy using optimized LentiHBBT87Qvector in two patients with transfusion dependent β-thalassemia

Increasing Gene Editing Efficiency via CRISPR/Cas9- or Cas12a-Mediated Knock-In in Primary Human T Cells

Gene therapy for adenosine deaminase severe combined immune deficiency—An unexpected journey of four decades

Contact Info

Product

Resources

About

Gene therapy using optimized LentiHBB^T87Qvector in two patients with transfusion dependent β-thalassemia

Gene therapy using optimized LentiHBB^T87Qvector in two patients with transfusion dependent β-thalassemia