AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival.
Cytokines
Immunotherapy
T-Lymphocytes
Translational Medical Research
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
accepted:
27
07
2023
medline:
18
9
2023
pubmed:
15
9
2023
entrez:
14
9
2023
Statut:
ppublish
Résumé
AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets. VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale. AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP. Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse.
Sections du résumé
BACKGROUND
AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets.
METHODS
VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale.
RESULTS
AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP.
CONCLUSION
Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse.
Identifiants
pubmed: 37709295
pii: jitc-2023-007002
doi: 10.1136/jitc-2023-007002
pmc: PMC10503365
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Adaptor Proteins, Signal Transducing
0
Angiogenesis Inhibitors
0
Antigens, CD19
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Department of Health
ID : IS-BTU-0214-10074
Pays : United Kingdom
Informations de copyright
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: MAP owns stock in and is employed Autolus Therapeutics; an inventor on patents licensed to Autolus Therapeutics to which he receives a share of revenues. KSP share holder and consultant of Autolus Therapeutics. CR speaker fees and advisory boards for Novartis, Kite/Gilead, Amgen and BMS/Celgene.
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