Next-generation BCMA-targeted chimeric antigen receptor CARTemis-1: the impact of manufacturing procedure on CAR T-cell features.
CAR-T
Immunophenotype monitoring
Manufacturing procedure
Multiple myeloma
anti-BCMA
Journal
Cellular oncology (Dordrecht, Netherlands)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
27 Aug 2024
27 Aug 2024
Historique:
accepted:
09
08
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
27
8
2024
Statut:
aheadofprint
Résumé
CAR therapy targeting BCMA is under investigation as treatment for multiple myeloma. However, given the lack of plateau in most studies, pursuing more effective alternatives is imperative. We present the preclinical and clinical validation of a new optimized anti-BCMA CAR (CARTemis-1). In addition, we explored how the manufacturing process could impact CAR-T cell product quality and fitness. CARTemis-1 optimizations were evaluated at the preclinical level both, in vitro and in vivo. CARTemis-1 generation was validated under GMP conditions, studying the dynamics of the immunophenotype from leukapheresis to final product. Here, we studied the impact of the manufacturing process on CAR-T cells to define optimal cell culture protocol and expansion time to increase product fitness. Two different versions of CARTemis-1 with different spacers were compared. The longer version showed increased cytotoxicity. The incorporation of the safety-gene EGFRt into the CARTemis-1 structure can be used as a monitoring marker. CARTemis-1 showed no inhibition by soluble BCMA and presents potent antitumor effects both in vitro and in vivo. Expansion with IL-2 or IL-7/IL-15 was compared, revealing greater proliferation, less differentiation, and less exhaustion with IL-7/IL-15. Three consecutive batches of CARTemis-1 were produced under GMP guidelines meeting all the required specifications. CARTemis-1 cells manufactured under GMP conditions showed increased memory subpopulations, reduced exhaustion markers and selective antitumor efficacy against MM cell lines and primary myeloma cells. The optimal release time points for obtaining the best fit product were > 6 and < 10 days (days 8-10). CARTemis-1 has been rationally designed to increase antitumor efficacy, overcome sBCMA inhibition, and incorporate the expression of a safety-gene. The generation of CARTemis-1 was successfully validated under GMP standards. A phase I/II clinical trial for patients with multiple myeloma will be conducted (EuCT number 2022-503063-15-00).
Identifiants
pubmed: 39192092
doi: 10.1007/s13402-024-00984-0
pii: 10.1007/s13402-024-00984-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Instituto de Salud Carlos III
ID : PFIS-FI21/00222
Organisme : Instituto de Salud Carlos III
ID : CD21/00162
Organisme : Instituto de Salud Carlos III
ID : CP23/00139
Organisme : Consejeria de Salud y Familias, Junta de Andalucia
ID : RH*-0042-2020
Organisme : Consejeria de Universidad, Investigacion e Innovacion, Junta de Andalucia
ID : DOC_01652
Informations de copyright
© 2024. The Author(s).
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