Next-generation BCMA-targeted chimeric antigen receptor CARTemis-1 : the impact of manufacturing procedure on CAR T-cell features
Sierro-Martínez, Belén (Instituto de Biomedicina de Sevilla)
Escamilla Gómez, Virginia (Instituto de Biomedicina de Sevilla)
Pérez-Ortega, Laura (Instituto de Biomedicina de Sevilla)
Guijarro-Albaladejo, Beatriz (Instituto de Biomedicina de Sevilla)
Hernández-Díaz, Paola (Instituto de Biomedicina de Sevilla)
de la Rosa-Garrido, Maria (Instituto de Biomedicina de Sevilla)
Lara-Chica, Maribel (Instituto de Biomedicina de Sevilla)
Rodríguez Gil, Alfonso (Instituto de Biomedicina de Sevilla)
Reguera-Ortega, Juan Luis (Instituto de Biomedicina de Sevilla)
Sanoja-Flores, Luzalba (Instituto de Biomedicina de Sevilla)
Arribas-Arribas, Blanca (Universidad de Sevilla)
Montiel-Aguilera, M.Á. (Red Andaluza de diseño y traslación de Terapias Avanzadas)
Carmona, Gloria (Red Andaluza de diseño y traslación de Terapias Avanzadas)
Robles, Maria Jose (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Caballero Velazquez, Teresa (Instituto de Biomedicina de Sevilla)
Briones Meijide, Javier (Institut de Recerca Sant Pau)
Einsele, Hermann (Universitätsklinikum Würzburg)
Hudecek, Michael (Universitätsklinikum Würzburg)
Pérez-Simón, José Antonio (Instituto de Biomedicina de Sevilla)
García-Guerrero, Estefanía (Instituto de Biomedicina de Sevilla)
Universitat Autònoma de Barcelona

Date:	2025
Abstract:	Purpose: 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. Methods: 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. Results: 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.
Grants:	Instituto de Salud Carlos III PI20/01792
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	CAR-T ; Immunophenotype monitoring ; Manufacturing procedure ; Multiple myeloma ; Anti-BCMA
Published in:	Cellular oncology (2011), Vol. 48 Núm. 1 (february 2025) , p. 219-237, ISSN 2211-3436

DOI: 10.1007/s13402-024-00984-0
PMID: 39192092

19 p, 8.7 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles