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Hematopoietic stem cell- and induced pluripotent stem cell-derived CAR-NK cells as reliable cell-based therapy solutions.

ABSTRACT: Hematopoietic stem cell- (HSC) and induced pluripotent stem (iPS) cell-derived natural killer (NK) cells containing engineered functions, such as chimeric antigen receptors (CAR), offer great promise for the treatment of seemingly incurable oncological malignancies. Today, some of the main challenges of CAR cell-based therapeutics are the long manufacturing time and safety of the cell sources used. Additional challenges include avoiding graft vs host disease (GVHD) and cytokine release syndrome (CRS). Here, we show compelling evidence for the use of NK cell therapeutics as a reliable off-the-shelf option, as they address key issues. Furthermore, we highlight how iPS cells and directed differentiation toward HSC and NK cells address industrial scalability and safety.

SUBMITTER: Arias J

PROVIDER: S-EPMC8235144 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Hematopoietic stem cell- and induced pluripotent stem cell-derived CAR-NK cells as reliable cell-based therapy solutions.

Arias Jonathan J Yu Jingwei J Varshney Mukesh M Inzunza Jose J Nalvarte Ivan I

Stem cells translational medicine 20210226 7

Hematopoietic stem cell- (HSC) and induced pluripotent stem (iPS) cell-derived natural killer (NK) cells containing engineered functions, such as chimeric antigen receptors (CAR), offer great promise for the treatment of seemingly incurable oncological malignancies. Today, some of the main challenges of CAR cell-based therapeutics are the long manufacturing time and safety of the cell sources used. Additional challenges include avoiding graft vs host disease (GVHD) and cytokine release syndrome ...[more]

PMID: 33634954

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Project description:BackgroundChimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy.MethodsWe conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes.ResultsAll patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46% of the patients. CAR-T therapy was associated with a higher incidence of biphasic, late-onset, or prolonged cytopenias. Survival analysis indicated that neutropenia and lymphopenia tended to be associated with better prognosis, whereas thrombocytopenia tended to be related to poorer outcomes. Through animal experiments, we discovered that MSCs infusion boosted HSCs and their long-term subpopulations, enhancing hematopoietic recovery, particularly in the megakaryocyte lineage, and mitigating bone marrow damage. Importantly, both in vitro and in vivo experiments demonstrated that MSCs did not compromise the activity or antitumor efficacy of CAR-T cells.ConclusionsOur findings propose MSCs infusion as a promising strategy to address cytopenias, particularly thrombocytopenia, after CAR-T therapy. This approach could help overcome certain limitations of cellular immunotherapy by enhancing hematopoietic recovery without compromising the efficacy of CAR-T cells.Highlights1 Cytopenia is a frequently observed adverse effect following CAR-T therapy, and it is often characterized by biphasic and prolonged patterns. 2 MSCs play a critical role in promoting hematopoietic recovery and mitigating bone marrow damage in a murine model of CAR-T therapy 3 The activity and antitumor efficacy of CAR-T cells were not impaired by MSCs.

Dataset Information

Hematopoietic stem cell- and induced pluripotent stem cell-derived CAR-NK cells as reliable cell-based therapy solutions.

Publications

Hematopoietic stem cell- and induced pluripotent stem cell-derived CAR-NK cells as reliable cell-based therapy solutions.

Similar Datasets

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