Il-15 enhances the persistence and function of bcma-targeting car-t cells compared to il-2 or il-15/il-7 by limiting car-t cell dysfunction and differentiation
Battram, Anthony M. (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Bachiller, Mireia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Lopez, Victor (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Fernandez de Larrea Rodriguez, Carlos (Universitat de Barcelona. Departament de Medicina)
Urbano Ispizua, Álvaro (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Martín-Antonio, B (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)

Fecha:	2021
Resumen:	Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the treatment of B-lymphoid malignancies. For multiple myeloma (MM), B-cell maturation antigen (BCMA)-targeted CAR-T cells have achieved outstanding complete response rates, but unfortunately, patients often relapse within a year of receiving the therapy. Increased persistence and reduced dysfunction are crucial features that enhance the durability of CAR-T cell responses. One of the factors that influence CAR-T cell in vivo longevity and loss of function, but which has not yet been extensively studied for BCMA-directed CAR-T cells, are the cytokines used during their production. We here compared the impact of IL-2, IL-15 and a combination of IL-15/IL-7 on the phenotype and function of ARI2h, an academic BCMA-directed CAR-T cell that is currently being administered to MM patients. For this study, flow cytometry, in vitro cytotoxicity assays and analysis of cytokine release were performed. In addition, ARI2h cells expanded with IL-2, IL-15, or IL-15/IL-7 were injected into MM tumor-bearing mice to assess their in vivo efficacy. We demonstrated that each of the cytokine conditions was suitable for the expansion of ARI2h cells, with clear in vitro activity. Strikingly, however, IL-15-produced ARI2h cells had improved in vivo efficacy and persistence. When explored further, it was found that IL-15 drove a less-differentiated ARI2h phenotype, ameliorated parameters related to CAR-T cell dysfunction, and lowered the release of cytokines potentially involved in cytokine release syndrome and MM progression. Moreover, we observed that IL-15 was less potent in inducing T cell senescence and DNA damage accumulation, both of which may contribute to an unfavorable CAR-T cell phenotype. These findings show the superiority of IL-15 to IL-2 and IL-15/IL-7 in the quality of anti-BCMA CAR-T cells, particularly their efficacy and persistence, and as such, could improve the duration of responses if applied to the clinical production of CAR-T cells for patients.
Ayudas:	"la Caixa" Foundation CP042702 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-00792 Instituto de Salud Carlos III ICI19/00025 Instituto de Salud Carlos III PI17/01043 Instituto de Salud Carlos III PI19/00669
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	CAR-T cells ; Multiple myeloma ; IL-2 ; IL-15 ; IL-7 ; BCMA ; Senescence
Publicado en:	Cancers, Vol. 13 Núm. 14 (february 2021) , art. 3534, ISSN 2072-6694

DOI: 10.3390/cancers13143534
PMID: 34298748

20 p, 5.5 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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