CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial.
Adolescent
Adult
Antigens, CD19
/ genetics
Child
Child, Preschool
Female
Humans
Immunotherapy
/ adverse effects
Immunotherapy, Adoptive
/ adverse effects
Infant
Male
Pediatrics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
/ therapy
Progression-Free Survival
Receptors, Chimeric Antigen
/ administration & dosage
Sialic Acid Binding Ig-like Lectin 2
/ genetics
Young Adult
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
19
03
2021
accepted:
09
08
2021
pubmed:
14
10
2021
medline:
16
11
2021
entrez:
13
10
2021
Statut:
ppublish
Résumé
Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.
Identifiants
pubmed: 34642489
doi: 10.1038/s41591-021-01497-1
pii: 10.1038/s41591-021-01497-1
pmc: PMC8516648
doi:
Substances chimiques
Antigens, CD19
0
Receptors, Chimeric Antigen
0
Sialic Acid Binding Ig-like Lectin 2
0
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1797-1805Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/D014301/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/E005896/1
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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