Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1
Salima Hacein-Bey-Abina,Alexandrine Garrigue,Gary P. Wang,Jean Soulier,Annick Lim,Estelle Morillon,Emmanuelle Clappier,Laure Caccavelli,Eric Delabesse,Kheira Beldjord,Vahid Asnafi,Elizabeth Macintyre,Liliane Dal Cortivo,Isabelle Radford,Nicole Brousse,François Sigaux,Despina Moshous,Julia Hauer,Arndt Borkhardt,Bernd H. Belohradsky,Uwe Wintergerst,Maria C. Velez,Lily E. Leiva,Ricardo U. Sorensen,NM Wulffraat,Stéphane Blanche,Frederic D. Bushman,Alain Fischer,Marina Cavazzana-Calvo +28 more
TLDR
These findings functionally specify a genetic network that controls growth in T cell progenitors and led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth.Abstract:
Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.read more
Citations
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Chimeric Antigen Receptor Therapy.
Carl H. June,Michel Sadelain +1 more
TL;DR: This review addresses T-cell engineering and synthetic immunity, with a focus on producing durable remissions in patients with treatment-refractory tumors, aboutimeric Antigen Receptor T Cells.
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Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
Marina Cavazzana-Calvo,Emmanuel Payen,Olivier Negre,Gary P. Wang,Kathleen M. Hehir,Floriane Fusil,Julian D. Down,Maria Denaro,Troy Brady,Karen A. Westerman,Resy Cavallesco,Beatrix Gillet-Legrand,Laure Caccavelli,Laure Caccavelli,Riccardo Sgarra,Leila Maouche-Chretien,Françoise Bernaudin,Robert Girot,Ronald Dorazio,Geert Jan Mulder,Axel Polack,Arthur Bank,Jean Soulier,Jérôme Larghero,Nabil Kabbara,Bruno Dalle,Bernard Gourmel,Gérard Socié,Stany Chrétien,Stany Chrétien,Nathalie Cartier,Patrick Aubourg,Alain Fischer,Alain Fischer,Kenneth Cornetta,Frédéric Galactéros,Yves Beuzard,Eliane Gluckman,Frederick D. Bushman,Salima Hacein-Bey-Abina,Salima Hacein-Bey-Abina,Philippe Leboulch +41 more
TL;DR: It is shown that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months.
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Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy.
Alessandra Biffi,Eugenio Montini,Laura Lorioli,Martina Cesani,Francesca Fumagalli,Tiziana Plati,Cristina Baldoli,Sabata Martino,Andrea Calabria,Sabrina Canale,Fabrizio Benedicenti,Giuliana Vallanti,Luca Biasco,Simone Leo,Nabil Kabbara,Gianluigi Zanetti,William B. Rizzo,Nalini Mehta,Maria Pia Cicalese,Miriam Casiraghi,Jaap Jan Boelens,Ubaldo Del Carro,David J. Dow,Manfred Schmidt,Andrea Assanelli,Victor Neduva,Clelia Di Serio,Elia Stupka,Jason P. Gardner,Christof von Kalle,Claudio Bordignon,Claudio Bordignon,Fabio Ciceri,Attilio Rovelli,Maria Grazia Roncarolo,Alessandro Aiuti,Maria Sessa,Luigi Naldini +37 more
TL;DR: The reconstitution of ARSA activity in the cerebrospinal fluid and the arrested progression of neurodegenerative disease in the three treated patients demonstrate that the transplanted cells, or their progeny, can seed the nervous system and deliver therapeutic levels of active enzyme.
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Toxicities of chimeric antigen receptor T cells: recognition and management.
TL;DR: The toxicities caused by CAR T cells are described and the published approaches used to manage toxicities are reviewed, with guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy presented.
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Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency
Alessandro Aiuti,Federica Cattaneo,Stefania Galimberti,Ulrike Benninghoff,Barbara Cassani,Luciano Callegaro,Samantha Scaramuzza,Grazia Andolfi,Massimiliano Mirolo,Immacolata Brigida,Antonella Tabucchi,Filippo Carlucci,Martha M. Eibl,Memet Aker,Shimon Slavin,Hamoud Al-Mousa,Abdulaziz Al Ghonaium,Alina Ferster,Andrea Duppenthaler,Luigi D. Notarangelo,Uwe Wintergerst,Rebecca H. Buckley,Marco Bregni,Sarah Marktel,Maria Grazia Valsecchi,Pier Luca Rossi,Fabio Ciceri,Roberto Miniero,Claudio Bordignon,Claudio Bordignon,Maria Grazia Roncarolo +30 more
TL;DR: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency and effective protection against infections and improvement in physical development made a normal lifestyle possible.
References
More filters
Journal ArticleDOI
Genome sequencing in microfabricated high-density picolitre reactors
Marcel Margulies,Michael Egholm,William E. Altman,Said Attiya,Joel S. Bader,Lisa A. Bemben,Jan Berka,Michael S. Braverman,Yi-Ju Chen,Zhoutao Chen,Scott Dewell,Lei Du,J. M. Fierro,Xavier V. Gomes,Brian C. Godwin,Wen He,Scott Edward Helgesen,Chun Heen Ho,Gerard P. Irzyk,Szilveszter C. Jando,Maria L. I. Alenquer,Thomas P. Jarvie,Kshama B. Jirage,Jong-Bum Kim,James R. Knight,Janna R. Lanza,John H. Leamon,Steven Lefkowitz,Ming Lei,Jing Li,Kenton Lohman,Hong Lu,Vinod Makhijani,Keith Mcdade,Michael P. McKenna,Eugene W. Myers,Elizabeth Nickerson,John Nobile,Ramona Plant,Bernard P. Puc,Michael T. Ronan,George T. Roth,Gary J. Sarkis,Jan Fredrik Simons,John Simpson,Maithreyan Srinivasan,Karrie R. Tartaro,Alexander Tomasz,Kari A. Vogt,Greg A. Volkmer,Shally H. Wang,Yong Wang,Michael P. Weiner,Pengguang Yu,Richard F. Begley,Jonathan M. Rothberg +55 more
TL;DR: A scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments with 96% coverage at 99.96% accuracy in one run of the machine is described.
Journal ArticleDOI
LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.
Salima Hacein-Bey-Abina,C von Kalle,C von Kalle,Manfred Schmidt,Matthew P. McCormack,NM Wulffraat,Philippe Leboulch,Annick Lim,Cameron S. Osborne,R. Pawliuk,Estelle Morillon,R. Sorensen,A. Forster,Peter Fraser,Jeffrey I. Cohen,G de Saint Basile,Ian E. Alexander,Uwe Wintergerst,Thierry Frebourg,Alain Aurias,Dominique Stoppa-Lyonnet,Serge Romana,I. Radford-Weiss,Fabian Gross,Françoise Valensi,Eric Delabesse,Elizabeth Macintyre,F. Sigaux,Jean Soulier,L. E. Leiva,Manuela Wissler,Claudia Prinz,Terence H. Rabbitts,F. Le Deist,Alain Fischer,Marina Cavazzana-Calvo +35 more
TL;DR: Retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.
Journal ArticleDOI
Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
Andrew P. Weng,Andrew P. Weng,Adolfo A. Ferrando,Adolfo A. Ferrando,Woojoong Lee,Woojoong Lee,John P. Morris,John P. Morris,Lewis B. Silverman,Lewis B. Silverman,Cheryll Sanchez-Irizarry,Cheryll Sanchez-Irizarry,Stephen C. Blacklow,Stephen C. Blacklow,A. Thomas Look,A. Thomas Look,Jon C. Aster,Jon C. Aster +17 more
TL;DR: These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.
Journal ArticleDOI
Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease
Marina Cavazzana-Calvo,Hacein-Bey S,Geneviève de Saint Basile,Fabian Gross,Eric Yvon,Patrick Nusbaum,Françoise Selz,Christophe Hue,Stéphanie Certain,Jean-Laurent Casanova,Philippe Bousso,Françoise Le Deist,Alain Fischer +12 more
TL;DR: A gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective gammac Moloney retrovirus-derived vector and ex vivo infection of CD34+ cells, which provided full correction of disease phenotype and clinical benefit.
Journal ArticleDOI
HIV-1 Integration in the Human Genome Favors Active Genes and Local Hotspots
Astrid R. W Schroder,Paul Shinn,Huaming Chen,Charles C. Berry,Joseph R. Ecker,Frederic D. Bushman +5 more
TL;DR: Global analysis of cellular transcription indicated that active genes were preferential integration targets, particularly genes that were activated in cells after infection by HIV-1, and this data suggests how selective targeting promotes aggressive HIV replication.
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