Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies

Heipertz, Erica L.; Zynda, Evan R.; Stav-Noraas, Tor Espen; Hungler, Andrew D.; Boucher, Shayne; Kaur, Navjot; Vemuri, Mohan C.

doi:10.3389/fimmu.2021.732135

Cited by 108 publications

(81 citation statements)

References 132 publications

(190 reference statements)

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“…Natural killer (NK) cells are appealing cells for immunotherapy because they are very potent effector lymphocytes of the innate immune system that can attack and kill many different tumor target cells without prior sensitization [ 1 – 3 ]. Studies show that some cytotoxic immune cells, including T- and NK cells, are capable of killing multiple target cells, sequentially, in a process termed serial killing [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Optimizing NK-92 serial killers: gamma irradiation, CD95/Fas-ligation, and NK or LAK attack limit cytotoxic efficacy

et al. 2022

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Background The NK cell line NK-92 and its genetically modified variants are receiving attention as immunotherapies to treat a range of malignancies. However, since NK-92 cells are themselves tumors, they require irradiation prior to transfer and are potentially susceptible to attack by patients’ immune systems. Here, we investigated NK-92 cell-mediated serial killing for the effects of gamma-irradiation and ligation of the death receptor Fas (CD95), and NK-92 cell susceptibility to attack by activated primary blood NK cells. Methods To evaluate serial killing, we used 51Cr-release assays with low NK-92 effector cell to target Raji, Daudi or K562 tumor cell (E:T) ratios to determine killing frequencies at 2-, 4-, 6-, and 8-h. Results NK-92 cells were able to kill up to 14 Raji cells per NK-92 cell in 8 h. NK-92 cells retained high cytotoxic activity immediately after irradiation with 10 Gy but the cells surviving irradiation lost > 50% activity 1 day after irradiation. Despite high expression of CD95, NK-92 cells maintained their viability following overnight Fas/CD95-ligation but lost some cytotoxic activity. However, 1 day after irradiation, NK-92 cells were more susceptible to Fas ligation, resulting in decreased cytotoxic activity of the cells surviving irradiation. Irradiated NK-92 cells were also susceptible to killing by both unstimulated and IL-2 activated primary NK cells (LAK). In contrast, non-irradiated NK-92 cells were more resistant to attack by NK and LAK cells. Conclusions Irradiation is deleterious to both the survival and cytotoxicity mediated by NK-92 cells and renders the NK-92 cells susceptible to Fas-initiated death and death initiated by primary blood NK cells. Therefore, replacement of irradiation as an antiproliferative pretreatment and genetic deletion of Fas and/or NK activation ligands from adoptively transferred cell lines are indicated as new approaches to increase therapeutic efficacy.

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Section: Introductionmentioning

confidence: 99%

Optimizing NK-92 serial killers: gamma irradiation, CD95/Fas-ligation, and NK or LAK attack limit cytotoxic efficacy

et al. 2022

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“…The large success and progress of chimeric antigen receptor (CAR)-engineered T cells in cancer immunotherapy ( 73 ) boosted the development of CAR-NK cells, which are currently being tested in multiple clinical trials ( 14 , 14 , 74 ). Interestingly, CAR technology can be combined with CIML NK cells to further enhance their functionality.…”

Section: Cytokine-induced Memory-like (Ciml) Nk Cellsmentioning

confidence: 99%

Cytokine-Induced Memory-Like NK Cells: From the Basics to Clinical Applications

et al. 2022

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Natural killer (NK) cells are lymphocytes with a key role in the defense against viral infections and tumor cells. Although NK cells are classified as innate lymphoid cells (ILCs), under certain circumstances they exhibit adaptive and memory-like features. The latter may be achieved, among others, by a brief stimulation with interleukin (IL)-12, IL-15 and IL-18. These cytokine-induced memory-like (CIML) NK cells resemble the trained immunity observed in myeloid cells. CIML NK cells undergo transcriptional, epigenetic and metabolic reprogramming that, along with changes in the expression of cell surface receptors and components of cytotoxic granules, are responsible for their enhanced effector functions after a resting period. In addition, these memory-like NK cells persist for a long time, which make them a good candidate for cancer immunotherapy. Currently, several clinical trials are testing CIML NK cells infusions to treat tumors, mostly hematological malignancies. In relapse/refractory acute myeloid leukemia (AML), the adoptive transfer of CIML NK cells is safe and complete clinical remissions have been observed. In our review, we sought to summarize the current knowledge about the generation and molecular basis of NK cell memory-like responses and the up-to-date results from clinical trials with CIML NK cells.

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“…NK cells, in contrast to T cells, can be obtained from allogeneic sources, including umbilical cord blood, human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), peripheral blood, and NK-92 cell lines [ 101 ]. Obtaining enough NK cells for engineering remains a challenge to CAR NK cell development, due to the unique challenges associated with each source.…”

Section: Car Nk Cellsmentioning

confidence: 99%

Alternative CAR Therapies: Recent Approaches in Engineering Chimeric Antigen Receptor Immune Cells to Combat Cancer

et al. 2022

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For nearly three decades, chimeric antigen receptors (CARs) have captivated the interest of researchers seeking to find novel immunotherapies to treat cancer. CARs were first designed to work with T cells, and the first CAR T cell therapy was approved to treat B cell lymphoma in 2017. Recent advancements in CAR technology have led to the development of modified CARs, including multi-specific CARs and logic gated CARs. Other immune cell types, including natural killer (NK) cells and macrophages, have also been engineered to express CARs to treat cancer. Additionally, CAR technology has been adapted in novel approaches to treating autoimmune disease and other conditions and diseases. In this article, we review these recent advancements in alternative CAR therapies and design, as well as their mechanisms of action, challenges in application, and potential future directions.

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Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies

Cited by 108 publications

References 132 publications

Optimizing NK-92 serial killers: gamma irradiation, CD95/Fas-ligation, and NK or LAK attack limit cytotoxic efficacy

Optimizing NK-92 serial killers: gamma irradiation, CD95/Fas-ligation, and NK or LAK attack limit cytotoxic efficacy

Cytokine-Induced Memory-Like NK Cells: From the Basics to Clinical Applications

Alternative CAR Therapies: Recent Approaches in Engineering Chimeric Antigen Receptor Immune Cells to Combat Cancer

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