“Built‐in” PD‐1 blocker to rescue NK‐92 activity from PD‐L1–mediated tumor escape mechanisms

Mensali, Nadia; Dillard, Pierre; Fayzullin, Artem; Köksal, Hakan; Gaudernack, Gustav; Kvalheim, Gunnar; Inderberg, Else Marit; Wälchli, Sébastien

doi:10.1096/fj.202100025r

Cited by 6 publications

(5 citation statements)

References 92 publications

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“…Our results are consistent with reports that NK cells combined with PD-L1 inhibitors have good antitumor effects against the background of PD-L1 + tumor cells 48 , 49 , 72 . In addition, the number of infiltrating CAR-NK cells increased after the addition of anti-PD-L1 in our study, and anti-PD-L1 prolonged the persistent activity of CAR-NK cells in tumors, which was consistent with related reports 73 . It was also confirmed that anti-PD-L1 relies on CAR-NK cells to function 31 , 49 .…”

Section: Discussionsupporting

confidence: 93%

NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer

Li,

Hu,

Lian

et al. 2024

Int. J. Biol. Sci.

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Background : The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR-NK cell efficacy. Claudin-6 (CLDN6) has been reported to be overexpressed in ovarian cancer and may be an attractive target for CAR-NK cells immunotherapy. However, the feasibility of using anti-CLDN6 CAR-NK cells to treat ovarian cancer remains to be explored. Methods : CLDN6 expression in primary human ovarian cancer, normal tissues and cell lines were detected by immunohistochemistry and western blot. Two types of third-generation CAR NK-92MI cells targeting CLDN6, CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) and CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB) were constructed by lentivirus transfection, sorted by flow cytometry and verified by western blot and qPCR. OVCAR-3, SK-OV-3, A2780, Hey and PC-3 cells expressing the GFP and luciferase genes were transduced. Subcutaneous and intraperitoneal tumor models were established via NSG mice. The ability of CLDN6-CAR NK cells to kill CLDN6-positive ovarian cancer cells were evaluated in vitro and in vivo by live cell imaging and bioluminescence imaging. Results : Both CLDN6-CAR1 and CLDN6-CAR2 NK-92MI cells could specifically killed CLDN6-positive ovarian cancer cells (OVCAR-3, SK-OV-3, A2780 and Hey), rather than CLDN6 negative cell (PC-3), in vitro. CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) exhibited stronger cytotoxicity than CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB). Furthermore, CLDN6-CAR1 NK cells could effectively eliminate ovarian cancer cells in subcutaneous and intraperitoneal tumor models. More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti-PD-L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. Conclusions : These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.

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Section: Discussionsupporting

confidence: 93%

NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer

Li,

Hu,

Lian

et al. 2024

Int. J. Biol. Sci.

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“…In addition to the aforementioned strategies to prevent NK cell inhibitory interactions with cancer cells by immune checkpoints or with immunosuppressive soluble factors, dominant-negative receptors have also been designed ( 259 – 261 ). The expression of a dominant-negative TGF-βRII (DNRII) in UCB-NK cells allows the maintenance of the NKG2D and DNAM-1 expression levels and glioblastoma cell-specific lysis in the presence of TGF-β ( 260 ).…”

Section: Tumor Microenvironment: the Stumbling Block That Limits Car-...mentioning

confidence: 99%

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

et al. 2022

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Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point out the achievement of deep, high-quality responses, thus confirming its potential clinical use. Although CAR-NK cell therapy is not significantly affected by the loss or downregulation of its CAR tumor target, as in the case of CAR-T cell, a plethora of common additional tumor intrinsic or extrinsic mechanisms that could also disable NK cell function have been described. Therefore, considering lessons learned from CAR-T cell therapy, the emergence of CAR-NK cell therapy resistance can also be envisioned. In this review we highlight the processes that could be involved in its development, focusing on cytokine addiction and potential fratricide during manufacturing, poor tumor trafficking, exhaustion within the tumor microenvironment (TME), and NK cell short in vivo persistence on account of the limited expansion, replicative senescence, and rejection by patient’s immune system after lymphodepletion recovery. Finally, we outline new actively explored alternatives to overcome these resistance mechanisms, with a special emphasis on CRISPR/Cas9 mediated genetic engineering approaches, a promising platform to optimize CAR-NK cell function to eradicate refractory cancers.

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“…Even if there is no formal proof that NK cells are involved in immunosurveillance, NK cells have been shown to have antitumor effects in clinical studies. In several xenograft models in which human cancer cells are implanted in immunodeficient mice, the injection of human NK cells controls tumor elimination (44,45). Solid evidence for the targeting of human tumors by NK cells in patients has been provided by studies of allogeneic hematopoietic stem cell transplantation (HSCT), in which donor NK cells expressing inhibitory KIRs mismatched with the patient's cells for MHC class I (MHC-I) molecules because they recognized recipient myeloid leukemia cells as foreign cells (46).…”

Section: Role Of Nk Cells In Cancermentioning

confidence: 99%

Role of the ITAM-Bearing Receptors Expressed by Natural Killer Cells in Cancer

et al. 2022

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Natural Killer (NK) cells are innate lymphoid cells (ILCs) capable of recognizing and directly killing tumor cells. They also secrete cytokines and chemokines, which participate in the shaping of the adaptive response. NK cells identify tumor cells and are activated through a net positive signal from inhibitory and activating receptors. Several activating NK cell receptors are coupled to adaptor molecules containing an immunoreceptor tyrosine-based activation motif (ITAM). These receptors include CD16 and the natural cytotoxic receptors NKp46, NKp44, NKp30 in humans. The powerful antitumor NK cell response triggered by these activating receptors has made them attractive targets for exploitation in immunotherapy. In this review, we will discuss the different activating receptors associated with ITAM-bearing cell surface receptors expressed on NK cells, their modulations in the tumor context and the various therapeutic tools developed to boost NK cell responses in cancer patients.

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“Built‐in” PD‐1 blocker to rescue NK‐92 activity from PD‐L1–mediated tumor escape mechanisms

Cited by 6 publications

References 92 publications

NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer

NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

Role of the ITAM-Bearing Receptors Expressed by Natural Killer Cells in Cancer

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