Base-Edited CAR7 T Cells for Relapsed T-Cell Acute Lymphoblastic Leukemia.

Adolescent Child Female Humans Antigens, CD19 Antigens, CD7 CD52 Antigen Hematopoietic Stem Cell Transplantation / adverse effects Immunotherapy, Adoptive / adverse effects Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics Receptors, Antigen, T-Cell / genetics Recurrence Stem Cell Transplantation T-Lymphocytes

Journal

The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562

Informations de publication

Date de publication:
07 Sep 2023
Historique:
medline: 8 9 2023
pubmed: 14 6 2023
entrez: 14 6 2023
Statut: ppublish

Résumé

Cytidine deamination that is guided by clustered regularly interspaced short palindromic repeats (CRISPR) can mediate a highly precise conversion of one nucleotide into another - specifically, cytosine to thymine - without generating breaks in DNA. Thus, genes can be base-edited and rendered inactive without inducing translocations and other chromosomal aberrations. The use of this technique in patients with relapsed childhood T-cell leukemia is being investigated. We used base editing to generate universal, off-the-shelf chimeric antigen receptor (CAR) T cells. Healthy volunteer donor T cells were transduced with the use of a lentivirus to express a CAR with specificity for CD7 (CAR7), a protein that is expressed in T-cell acute lymphoblastic leukemia (ALL). We then used base editing to inactivate three genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively. We investigated the safety of these edited cells in three children with relapsed leukemia. The first patient, a 13-year-old girl who had relapsed T-cell ALL after allogeneic stem-cell transplantation, had molecular remission within 28 days after infusion of a single dose of base-edited CAR7 (BE-CAR7). She then received a reduced-intensity (nonmyeloablative) allogeneic stem-cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukemic remission. BE-CAR7 cells from the same bank showed potent activity in two other patients, and although fatal fungal complications developed in one patient, the other patient underwent allogeneic stem-cell transplantation while in remission. Serious adverse events included cytokine release syndrome, multilineage cytopenia, and opportunistic infections. The interim results of this phase 1 study support further investigation of base-edited T cells for patients with relapsed leukemia and indicate the anticipated risks of immunotherapy-related complications. (Funded by the Medical Research Council and others; ISRCTN number, ISRCTN15323014.).

Sections du résumé

BACKGROUND BACKGROUND
Cytidine deamination that is guided by clustered regularly interspaced short palindromic repeats (CRISPR) can mediate a highly precise conversion of one nucleotide into another - specifically, cytosine to thymine - without generating breaks in DNA. Thus, genes can be base-edited and rendered inactive without inducing translocations and other chromosomal aberrations. The use of this technique in patients with relapsed childhood T-cell leukemia is being investigated.
METHODS METHODS
We used base editing to generate universal, off-the-shelf chimeric antigen receptor (CAR) T cells. Healthy volunteer donor T cells were transduced with the use of a lentivirus to express a CAR with specificity for CD7 (CAR7), a protein that is expressed in T-cell acute lymphoblastic leukemia (ALL). We then used base editing to inactivate three genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively. We investigated the safety of these edited cells in three children with relapsed leukemia.
RESULTS RESULTS
The first patient, a 13-year-old girl who had relapsed T-cell ALL after allogeneic stem-cell transplantation, had molecular remission within 28 days after infusion of a single dose of base-edited CAR7 (BE-CAR7). She then received a reduced-intensity (nonmyeloablative) allogeneic stem-cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukemic remission. BE-CAR7 cells from the same bank showed potent activity in two other patients, and although fatal fungal complications developed in one patient, the other patient underwent allogeneic stem-cell transplantation while in remission. Serious adverse events included cytokine release syndrome, multilineage cytopenia, and opportunistic infections.
CONCLUSIONS CONCLUSIONS
The interim results of this phase 1 study support further investigation of base-edited T cells for patients with relapsed leukemia and indicate the anticipated risks of immunotherapy-related complications. (Funded by the Medical Research Council and others; ISRCTN number, ISRCTN15323014.).

Identifiants

DOI: 10.1056/NEJMoa2300709 PMID: 37314354
pubmed: 37314354
doi: 10.1056/NEJMoa2300709
doi:

Substances chimiques

Antigens, CD19 0
Antigens, CD7 0
CD52 Antigen 0
Receptors, Antigen, T-Cell 0

Banques de données

ISRCTN
['ISRCTN15323014']

Types de publication

Case Reports Clinical Trial, Phase I Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

899-910

Investigateurs

Waseem Qasim (W)
Christos Georgiadis (C)
Giorgio Ottaviano (G)
Hong Zhan (H)
Annie Etuk (A)
Syed Farhatullah (S)
Roland Preece (R)
Toni Braybrook (T)
Hala Aldahshan (H)
Ayad Eddaoudi (A)
Avijeet Mishra (A)
Jesmina James (J)
Kimberly Gilmour (K)
Arnold Aawuah (A)
Rebecca Thomas (R)
Stuart Adams (S)
Lana Mhaldien (L)
Soragia Gkazi (S)
Agnieszka Kubat (A)
Attia Hasnain (A)
Barry Flutter (B)
Ilaria Schena (I)
Batoul Ahmed (B)
Danielle Pinner (D)
Jan Chu (J)
Lindsey Williams (L)
Ka-Yuk Ko (KY)
Persis Amrolia (P)
Kanchan Rao (K)
Robert Chiesa (R)
Paul Veys (P)
Juliana Silva (J)
Giovanna Lucchini (G)
Arina Lazareva (A)
Milena Balasch Carulla (M)
Khushnuma Mullanfiroze (K)
Susan Staddon (S)
Rebecca O'Neill (R)
Philip Ancliff (P)
David O'Conner (D)
Sara Ghorashian (S)
Sujith Samarasinghe (S)
Anupama Rao (A)
Ajay Vora (A)
Jack Bartram (J)
Vesna Pavasovic (V)
Danny Cheng (D)
Sabine Domning (S)
Farzin Farzaneh (F)
Martin Sauer (M)
Axel Schambach (A)
Michael Heuser (M)
Arnold Kloos (A)
James Boot (J)
Eva Wozniak (E)
Charlse A Mien (CA)
Kaljit Bhuller (K)
Katharine Patrick (K)
Amrana Qureshi (A)
Daniel Steinbach (D)

Informations de copyright

Copyright © 2023 Massachusetts Medical Society.

Auteurs

Robert Chiesa (R)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Christos Georgiadis (C)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Farhatullah Syed (F)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Hong Zhan (H)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Annie Etuk (A)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Soragia Athina Gkazi (SA)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Roland Preece (R)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Giorgio Ottaviano (G)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Toni Braybrook (T)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Jan Chu (J)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Agnieszka Kubat (A)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Stuart Adams (S)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Rebecca Thomas (R)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Kimberly Gilmour (K)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

David O'Connor (D)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Ajay Vora (A)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.

Waseem Qasim (W)

From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.
ORCID: 0000-0001-8353-4494

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes B › Antigènes CD19 › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Antigènes CD7 › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigène CD52 › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Procédures de chirurgie opératoire › Transplantation › Transplantation cellulaire › Transplantation de cellules souches › Transplantation de cellules souches hématopoïétiques › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Techniques d'investigation › Techniques immunologiques › Immunisation passive › Transfert adoptif › Immunothérapie adoptive › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Leucémie lymphoïde › Leucémie-lymphome lymphoblastique à précurseurs B et T › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs aux antigènes › Récepteurs aux antigènes des cellules T › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Récidive › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Procédures de chirurgie opératoire › Transplantation › Transplantation cellulaire › Transplantation de cellules souches › Base-Edited CAR7 T Cells for Relapsed T-Cell...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Base-Edited CAR7 T Cells for Relapsed T-Cell...