NK cells enhance CAR-T cell antitumor efficacy by enhancing immune/tumor cells cluster formation and improving CAR-T cell fitness
Bachiller, Mireia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Pérez-Amill, Lorena (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Battram, Anthony M (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Carné, Sebastian Ciro (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Najjar, Amer (The University of Texas MD Anderson Cancer Center)
Verhoeyen, Els (Université Côte d'Azur)
Juan, Manel (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)
Universitat Autònoma de Barcelona

Date:	2021
Abstract:	Background Chimeric antigen receptor (CAR)-T cell immunotherapy has modified the concept of treatment in hematological malignancies. In comparison with pediatric patients, where responses are maintained over many years, older patients, such as those with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), present lower persistence of CAR-T cells that might be due to decreased fitness of T cells acquired with aging. Moreover, cord blood derived-NK cells (CB-NKs) and CAR-NK cells derived from CB-NK can be used ' off-the-shelf' as immune cells with antitumor properties for the treatment of cancer patients. However, to date, clinical studies have only demonstrated the safety of these therapies but not optimal efficacy. To confront the shortcomings of each therapy, we devised a novel approach consisting of simultaneous (CAR-)NK cell and CAR-T cell administration. In this setting, NK cells demonstrate an important immunoregulation of T cells that could be exploited to enhance the efficacy of CAR-T cells. Methods A combinatorial treatment based on either CAR-T and CAR-NK cells or CB-NK and CAR-T cells in two models of NHL and MM was performed. Antitumor efficacy was analyzed in vitro and in vivo, and parameters related to early activation, exhaustion and senescence of T cells were analyzed. Results We show that CAR-NK cells derived from CB-NK are only effective at high doses (high E:T ratio) and that their activity rapidly decreases over time in comparison with CAR-T cells. In comparison and to exploit the potential of ' off-the-shelf' CB-NK, we demonstrate that a low number of CB-NK in the CAR-T cell product promotes an early activation of CAR-T cells and their migration to MM cells leading to enhanced anti-MM efficacy. Moreover, cytokines related to CRS development were not increased, and importantly, CB-NK enhanced the fitness of both CAR pos and CAR neg T cells, promoting lower levels of exhaustion and senescence. Conclusion This study demonstrates a relevant immunoregulatory role of CB-NK collaborating with CAR-T cells to enhance their antitumor activity. A novel and different approach to consider in CAR-T cell immunotherapy studies is presented here with the goal to enhance the efficacy of the treatment.
Grants:	Instituto de Salud Carlos III PI17/01043 Instituto de Salud Carlos III PI20/00991 Instituto de Salud Carlos III PI18/00775
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
Published in:	Journal for immunotherapy of cancer, Vol. 9 Núm. 8 (25 2021) , p. 2866, ISSN 2051-1426

DOI: 10.1136/jitc-2021-002866
PMID: 34433634

21 p, 12.7 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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