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Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial

Abstract

β-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the β chain of hemoglobin. Here we report 6–8-year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34+ cells transduced with the TNS9.3.55 lentiviral globin vector after reduced-intensity conditioning (RIC) in a phase 1 clinical trial (NCT01639690). Patients were monitored for insertional mutagenesis and the generation of a replication-competent lentivirus (safety and tolerability of the infusion product after RIC—primary endpoint) and engraftment of genetically modified autologous CD34+ cells, expression of the transduced β-globin gene and post-transplant transfusion requirements (efficacy—secondary endpoint). No unexpected safety issues occurred during conditioning and cell product infusion. Hematopoietic gene marking was very stable but low, reducing transfusion requirements in two patients, albeit not achieving transfusion independence. Our findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment but underscore a minimum CD34+ cell transduction requirement for effective therapy. Moderate clonal expansions were associated with integrations near cancer-related genes, suggestive of non-erythroid activity of globin vectors in stem/progenitor cells. These correlative findings highlight the necessity of cautiously monitoring patients harboring globin vectors.

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Fig. 1: Multilineage engraftment of transduced cells in peripheral blood and bone marrow.
Fig. 2: Transfusion requirements and VCN in PBMCs.
Fig. 3: Long-term clonal abundance and succession in all patients.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. All requests for raw and analyzed data and materials are promptly reviewed by the corresponding author to verify if the request is subject to any intellectual property or confidentiality obligations. Patient-related data not included in this paper were generated as part of clinical trials and might be subject to patient confidentiality. Any data and materials that can be shared will be released via a material transfer agreement.

The following databases were used for oncogene definitions: the ‘Bushman lab oncogenes database’ (http://www.bushmanlab.org/links/genelists, version 5, June 2021) and four levels of The Cancer Genome Atlas version of the OncoVar database (https://oncovar.org, version 1.2, August 2020).

Sequence data were deposited in the National Center of Biotechnology Information’s Sequence Read Archive (SRA BioProject PRJNA705203). For integration site analysis relative to Gene Ontology, the ‘GO.db’ Bioconductor annotation data package, version 3.13.0, was used.

Code availability

Source code for manuscript analysis has been deposited in an archived format in the Zenodo code base (https://doi.org/10.5281/zenodo.4569099).

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Acknowledgements

The authors would first like to thank the patients and families of those included in the trial and further acknowledge the expert care provided to patients by staff members of the Department of Pediatrics at Memorial Sloan Kettering Cancer Center. We thank R. Cristantielli, G. Gunset and E. Bechard for their further assistance in making our patients’ journeys and their follow-up pleasant and efficient. This clinical trial was supported by the Stavros Niarchos Foundation (to M.S.), the Memorial Hospital Research Fund (to F.B.), the Leonardo Giambrone Foundation (to M.S.) and the Cooley’s Anemia Foundation (to M.S.) for transduction, biosafety and clinical costs, and Errant Gene Therapy (to M.S.) for the TNS9.3.55 vector lot, produced at the Center for Biomedicine and Genetics in Duarte, California, and the MSKCC Support Grant (P30 CA008748). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We also thank S. Avecilla, Q. He, C. Taylor, M. Fink, T. Wasielewska, S. Bartido, Y. Wang and the members of the Cell Therapy and Cell Engineering Facility who, for 7 years, have assisted in the manufacturing and monitoring of the CD34+ cell infusion products for our patients.

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Contributions

F.B., A.M., P.M., S.A., S.P., S.R., R.B., R.D.M. and L.P. were involved in patient care. X.W., J.Q., K.T., F.D. and L.S. performed transductions and biosafety assays. F.K. and C.T. assembled and analyzed clinical data. J.M.S. and A.C. reviewed vector and sequence data. J.K.E., P.H., A.M.R., V.A.C., H.A., S.R. and F.D.B. conducted vector integration site analyses. J.K.E. and F.D.B. modeled and analyzed IS data. A.G. oversaw HPLC analysis. E.B. oversaw HPLC studies. N.M. oversaw bone marrow FACS analyses. F.B., A.M., I.R. and M.S. designed the study. F.B., A.M., F.K., F.D.B., I.R. and M.S. wrote the manuscript.

Corresponding author

Correspondence to Michel Sadelain.

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Competing interests

The authors declare no competing interests. The TNS9.3.55 vector technology has been granted to Errant Gene Therapy without financial compensation.

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Peer review information Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Anna Maria Ranzoni and Javier Carmona were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Cell count recovery after conditioning and infusion of TNS9.3.55 transduced CD34 + HSPCs.

a, Platelet count (x109/l) after infusion. b, Absolute neutrophil count (x109/l) after infusion. Granulocyte colony stimulating factor (G-CSF) was administered for Patient 1 (day 13-16) and Patient 2 (day 16-18) during aplasia. Patient 1 received methylprednisolone intravenously for 3 consecutive days (day 16-18) for treating the engraftment syndrome.

Extended Data Fig. 2 β-globin expression in Patient 2 at 12 months post infusion.

a, HPLC chromatograms illustrating globin production of erythroid cells from four individual BFU-Es derived from bone marrow obtained from Patient 2 at 12 months post infusion. Top chromatograms: two representative examples from two individual, non-transduced BFU-E from Patient 2; lower chromatograms: two representative examples from two individual, transduced BFU-E from Patient 2. b, β-globin to α-globin ration in erythroids derived from untransduced and transduced HSCs obtained from Patient 2 at 12 months post infusion. The β/α expression ratio determined by HPLC in single BFU-Es increased from a mean of 0.11 to 0.38 in BFU-Es harboring a single copy of the integrated vector, representing a gain of 0.27. Results from BFU-Es derived from untransduced HSCs (n = 2; VCN = 0) and from BFU-Es derived from transduced HSCs (n = 4; VCN = 1). All data are mean ± s.e.m.

Extended Data Fig. 3 Erythropoietic maturation in bone marrow (Patient 2).

Terminal erythroid differentiation begins with proerythroblasts differentiating into basophilic, then polychromatic, then orthochromatic erythroblasts that enucleate to become reticulocytes. Each distinct stage of terminal human erythroid differentiation can be distinguished using a combination of cell surface markers for glycophorine A (GPA), band 3 and α4 integrin. a, Representative flow cytometry plot of band 3 vs α4-integrin of GPA + cells in normal erythropoiesis: proerythroblasts (I), early basophilic (II), late basophilic (III), polychromatic (IV), and orthochromatic erythroblasts (V) and reticulocytes (VI). The box plot represents the quantitation of the proportion of cells at each distinct stage of maturation after normalization based on total nucleated erythroid cells (I-V) as 100% as described in ref. 29. The left panel is adapted from ref. 29. b, Bone marrow erythroblasts from Patient 2 were analyzed by flow cytometry at 6, 12 and 24 months post infusion stained with GPA, α4-integrin, and band 3. Plot of band 3 vs α4-integrin of GPA + cells represents the quantitation of distinct stages of maturation of erythroblasts as described in a. c, Quantitation of the proportion of cells at each distinct stage of maturation after normalization to total nucleated erythroid cells (I-V).

Extended Data Fig. 4 Engraftment of transduced cells in bone marrow.

Vector copy number (VCN) in erythroid glycophorine A + (GPA + ) cells and CD45 + cells sorted from bone marrow of patients.

Extended Data Fig. 5 Gini and Shannon Index values.

Timepoints in months.

Extended Data Fig. 6 Annotation of the genes STAT3 and STAT5A on chromosome 17.

Illustration of a cluster of transgene integrations in the first intron of STAT3. Six integration sites were detected at year six, zero were detected pre-transplant. Four out of six integration sites detected were in the same transcriptional orientation as STAT3.

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Boulad, F., Maggio, A., Wang, X. et al. Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial. Nat Med 28, 63–70 (2022). https://doi.org/10.1038/s41591-021-01554-9

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