Preclinical Assessment of Suitable Natural Killer Cell Sources for Chimeric Antigen Receptor Natural Killer–Based “Off-the-Shelf” Acute Myeloid Leukemia Immunotherapies

Kloeß, Stephan; Oberschmidt, Olaf; Dahlke, Julia; Vu, Xuan‐Khang; Neudoerfl, Christine; Kloos, Arnold; Gardlowski, Tanja; Matthies, Nadine; Heuser, Michael; Meyer, Johann; Sauer, Martin; Falk, Christine S.; Koehl, Ulrike; Schambach, Axel; Morgan, Michael

doi:10.1089/hum.2018.247

Cited by 40 publications

(35 citation statements)

References 29 publications

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“…So far most of such efforts have focused on the NK-92 cell line, which was initially isolated from a non-Hodgkin lymphoma patient (151). NK-92 cells display features of activated primary NK cells and express many activating NK-cell receptors such as NKp30, NKp46, and NKG2D as well as high levels of granzymes A and B, but lack inhibitory NK-cell receptors except for KIR2DL4, Ig-like transcript 2 (ILT-2) and NKG2A/CD94 (151–155). General safety of repeated infusions of irradiated NK-92 cells at doses up to 10 10 cells/m 2 has been established in phase I clinical trials in patients with advanced cancers, with durable responses observed in some of the treated subjects (156–159).…”

Section: Advantages Of Car-nk Cells As Off-the-shelf Therapeuticsmentioning

confidence: 99%

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

et al. 2019

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Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with ex vivo activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.

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Section: Advantages Of Car-nk Cells As Off-the-shelf Therapeuticsmentioning

confidence: 99%

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

et al. 2019

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“…Different NK sources have been used to generate pre-clinically and clinically tested CAR NK cells, including cell lines such as NK-92 cells ( 45 ), cord blood-derived NK cells ( 43 , 46 ) and peripheral blood-derived NK cells ( 28 ). Of note, a recent landmark phase 1 and 2 study showed the feasibility of cord-blood-derived CAR NK cells to treat relapsed or refractory CD19 + B-cell cancers ( 43 ).…”

Section: Nk Cell Sourcesmentioning

confidence: 99%

“…This decision may also be influenced by the cell type (e.g., T cell, NK cell, other immune cells) to be used as the “living” drug as well as the temporal window in which these cell therapies should be active. Interestingly, CAR designs based on the T cell receptor also function in NK cells ( 26 – 28 ). However, this does not rule out the possibility to engineer immune cell type-specific CARs for optimal use in the chosen cell type ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Use of Cell and Genome Modification Technologies to Generate Improved “Off-the-Shelf” CAR T and CAR NK Cells

et al. 2020

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The broad success of adoptive immunotherapy to treat human cancer has resulted in a paradigm shift in modern medicine. Modification of autologous and allogenic immune cells with chimeric antigen receptors (CAR) designed to target specific antigens on tumor cells has led to production of CAR T and CAR NK cell therapies, which are ever more commonly introduced into cancer patient treatment protocols. While allogenic T cells may offer advantages such as improved anti-tumor activity, they also carry the risk of adverse reactions like graft-versus-host disease. This risk can be mitigated by use of autologous immune cells, however, the time needed for T and/or NK cell isolation, modification and expansion may be too long for some patients. Thus, there is an urgent need for strategies to robustly produce "off-the-shelf" CAR T and CAR NK cells, which could be used as a bridging therapy between cancer diagnosis or relapse and allogeneic transplantation. Advances in genome modification technologies have accelerated the generation of designer cell therapy products, including development of "off-the-shelf" CAR T cells for cancer immunotherapy. The feasibility and safety of such approaches is currently tested in clinical trials. This review will describe cell sources for CAR-based therapies, provide background of current genome editing techniques and the applicability of these approaches for generation of universal "off-the-shelf" CAR T and NK cell therapeutics.

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“…As for the sources of CAR-NK cells, a preclinical study showed that CD123-CAR-NK-92 cell lines represented better CAR effector cells than primary human donor CD123-CAR-NK cells in terms of cytotoxic activities [123].…”

Section: Car-nk Cell Therapymentioning

confidence: 99%

Natural killer cell-based immunotherapy for acute myeloid leukemia

Niu

2020

J Hematol Oncol

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Despite considerable progress has been achieved in the treatment of acute myeloid leukemia over the past decades, relapse remains a major problem. Novel therapeutic options aimed at attaining minimal residual disease-negative complete remission are expected to reduce the incidence of relapse and prolong survival. Natural killer cell-based immunotherapy is put forward as an option to tackle the unmet clinical needs. There have been an increasing number of therapeutic dimensions ranging from adoptive NK cell transfer, chimeric antigen receptor-modified NK cells, antibodies, cytokines to immunomodulatory drugs. In this review, we will summarize different forms of NK cell-based immunotherapy for AML based on preclinical investigations and clinical trials.

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Preclinical Assessment of Suitable Natural Killer Cell Sources for Chimeric Antigen Receptor Natural Killer–Based “Off-the-Shelf” Acute Myeloid Leukemia Immunotherapies

Cited by 40 publications

References 29 publications

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

Use of Cell and Genome Modification Technologies to Generate Improved “Off-the-Shelf” CAR T and CAR NK Cells

Natural killer cell-based immunotherapy for acute myeloid leukemia

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