Dataset Information

Clinical development of natural killer cells expressing chimeric antigen receptors.

ABSTRACT: Both natural killer (NK) cells and T cells demonstrate potent antitumor responses in many settings. NK cells, unlike T cells, are not the primary mediators of graft-versus-host disease (GVHD). Redirection of T cells with chimeric antigen receptors (CAR) has helped to overcome tumor escape from endogenous T cells. NK cells expressing CARs are a promising new therapy to treat malignancy. Clinical biomanufacturing of CAR NK cells can begin with NK cells derived from many different sources including adult peripheral blood-derived NK cells, cord blood-derived NK cells, cell line-derived NK cells, or stem cell-derived NK cells. Manufacturing protocols may include isolation of NK cells, activation, expansion, and genetic modification to express the chimeric antigen receptors. Clinical trials have tested both unmodified and CAR NK cells with encouraging results. The next stage in clinical development of CAR NK cells represents a highly exciting new frontier in clinical cell therapy as well as understanding basic NK cell biology. The purpose of this review is to provide the reader with a fundamental understanding of the core concepts in CAR NK cell manufacturing, specifically highlighting differences between CAR T cell manufacturing and focusing on future directions in the field.

SUBMITTER: Golden RJ

PROVIDER: S-EPMC10029926 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Clinical development of natural killer cells expressing chimeric antigen receptors.

Golden Ryan J RJ Fesnak Andrew D AD

Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 20210110 1

Both natural killer (NK) cells and T cells demonstrate potent antitumor responses in many settings. NK cells, unlike T cells, are not the primary mediators of graft-versus-host disease (GVHD). Redirection of T cells with chimeric antigen receptors (CAR) has helped to overcome tumor escape from endogenous T cells. NK cells expressing CARs are a promising new therapy to treat malignancy. Clinical biomanufacturing of CAR NK cells can begin with NK cells derived from many different sources including ...[more]

PMID: 33468407

Similar Datasets

Project description:Immunotherapy against solid tumors has long been hampered by the development of immunosuppressive tumor microenvironment, and the lack of a specific tumor-associated antigen that could be targeted in different kinds of solid tumors. Human leukocyte antigen G (HLA-G) is an immune checkpoint protein (ICP) that is neoexpressed in most tumor cells as a way to evade immune attack and has been recently demonstrated as a useful target for chimeric antigen receptor (CAR)-T therapy of leukemia by in vitro studies. Here, we design and test for targeting HLA-G in solid tumors using a CAR strategy. We developed a novel CAR strategy using natural killer (NK) cell as effector cells, featuring enhanced cytolytic effect via DAP12-based intracellular signal amplification. A single-chain variable fragment (scFv) against HLA-G is designed as the targeting moiety, and the construct is tested both in vitro and in vivo on four different solid tumor models. We also evaluated the synergy of this anti-HLA-G CAR-NK strategy with low-dose chemotherapy as combination therapy. HLA-G CAR-transduced NK cells present effective cytolysis of breast, brain, pancreatic, and ovarian cancer cells in vitro, as well as reduced xenograft tumor growth with extended median survival in orthotopic mouse models. In tumor coculture assays, the anti-HLA-G scFv moiety promotes Syk/Zap70 activation of NK cells, suggesting reversal of the HLA-G-mediated immunosuppression and hence restoration of native NK cytolytic functions. Tumor expression of HLA-G can be further induced using low-dose chemotherapy, which when combined with anti-HLA-G CAR-NK results in extensive tumor ablation both in vitro and in vivo. This upregulation of tumor HLA-G involves inhibition of DNMT1 and demethylation of transporter associated with antigen processing 1 promoter. Our novel CAR-NK strategy exploits the dual nature of HLA-G as both a tumor-associated neoantigen and an ICP to counteract tumor spread. Further ablation of tumors can be boosted when combined with administration of chemotherapeutic agents in clinical use. The readiness of this novel strategy envisions a wide applicability in treating solid tumors.

Project description:Owing to non-responsiveness of a high number of patients to the common melanoma therapies, seeking novel approaches seem as an unmet requirement. Chimeric antigen receptor (CAR) T cells were initially employed against recurrent or refractory B cell malignancies. However, advanced stages or pretreated patients have insufficient T cells (lymphopenia) amount for collection and clinical application. Additionally, this process is time-consuming and logistically cumbersome. Another limitation of this approach is toxicity and cytokine release syndrome (CRS) progress and neurotoxicity syndrome (NS). Natural killer (NK) cells are a versatile component of the innate immunity and have several advantages over T cells in the application for therapies such as availability, unique biological features, safety profile, cost effectiveness and higher tissue residence. Additionally, CAR NK cells do not develop Graft-versus-host disease (GvHD) and are independent of host HLA genotype. Notably, the NK cells number and activity is affected in the tumor microenvironment (TME), paving the way for developing novel approaches by enhancing their maturation and functionality. The CAR NK cells short lifespan is a double edge sword declining toxicity and reducing their persistence. Bispecific and Trispecific Killer Cell Engagers (BiKE and Trike, respectively) are emerging and promising immunotherapies for efficient antibody dependent cell cytotoxicity (ADCC). CAR NK cells have some limitations in terms of expanding and transducing NK cells from donors to achieve clinical response. Clinical trials are in scarcity regarding the CAR NK cell-based cancer therapies. The CAR NK cells short life span following irradiation before infusion limits their efficiency inhibiting their in vivo expansion. The CAR NK cells efficacy enhancement in terms of lifespan TME preparation and stability is a goal for melanoma treatment. Combination therapies using CAR NK cells and chemotherapy can also overcome therapy limitations.

Dataset Information

Clinical development of natural killer cells expressing chimeric antigen receptors.

Publications

Clinical development of natural killer cells expressing chimeric antigen receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets