A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
11
10
2022
accepted:
25
01
2023
medline:
21
4
2023
pubmed:
15
3
2023
entrez:
14
3
2023
Statut:
ppublish
Résumé
Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment ('high-risk antibiotics') prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.
Identifiants
pubmed: 36914893
doi: 10.1038/s41591-023-02234-6
pii: 10.1038/s41591-023-02234-6
pmc: PMC10121864
mid: NIHMS1887917
doi:
Substances chimiques
Receptors, Chimeric Antigen
0
Antigens, CD19
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
906-916Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL124112
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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