Enhanced Natural Killers with CISH and B2M Gene Knockouts Reveal Increased Cytotoxicity in Glioblastoma Primary Cultures

Yusubalieva, G. M.; Дашинимаев, Э. Б.; Gorchakov, Andrey A.; Kulemzin, Sergey V.; Brovkina, O. A.; Kalinkin, A. A.; Vinokurov, A. G.; Shirmanova, Marina V.; Taranin, Alexander V.; Baklaushev, Vladimir P.

doi:10.1134/s0026893322050156

Cited by 2 publications

(3 citation statements)

References 21 publications

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“…Here, we co-cultured CISH KO and control NK cells with an aggressive acute myeloid leukemia (AML) cell line, Molm-13, for 48 hours at multiple E:T ratios (Figure 1f) . Compared to control NK, CISH KO NK exhibited enhanced cytotoxicity against Molm-13 cells, in line with previous reports (Figure 1g) 34,52,53 .…”

Section: Resultssupporting

confidence: 92%

“…Our results showed that L-Kyn significantly reduced NK cell killing overall, however, AHR KO NK exhibited significantly higher levels of killing than control NK (Figure 1d & e and Supplement Figure 4a-d) . Due to its role in negative regulation of IL-15 signaling, several groups reported improved functionality of NK cells with CISH KO 34,52,53 . Here, we co-cultured CISH KO and control NK cells with an aggressive acute myeloid leukemia (AML) cell line, Molm-13, for 48 hours at multiple E:T ratios (Figure 1f) .…”

Section: Resultsmentioning

confidence: 99%

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Precision Enhancement of CAR-NK Cells through Non-Viral Engineering and Highly Multiplexed Base Editing

Wang,

Krueger,

Gilkey

et al. 2024

Preprint

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Natural killer (NK) cells' unique ability to kill transformed cells expressing stress ligands or lacking major histocompatibility complexes (MHC) has prompted their development for immunotherapy. However, NK cells have demonstrated only moderate responses against cancer in clinical trials and likely require advanced genome engineering to reach their full potential as a cancer therapeutic. Multiplex genome editing with CRISPR/Cas9 base editors (BE) has been used to enhance T cell function and has already entered clinical trials but has not been reported in human NK cells. Here, we report the first application of BE in primary NK cells to achieve both loss-of-function and gain-of-function mutations. We observed highly efficient single and multiplex base editing, resulting in significantly enhanced NK cell function. Next, we combined multiplex BE with non-viral TcBuster transposon-based integration to generate IL-15 armored CD19 CAR-NK cells with significantly improved functionality in a highly suppressive model of Burkitt's lymphoma both in vitro and in vivo. The use of concomitant non-viral transposon engineering with multiplex base editing thus represents a highly versatile and efficient platform to generate CAR-NK products for cell-based immunotherapy and affords the flexibility to tailor multiple gene edits to maximize the effectiveness of the therapy for the cancer type being treated.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Precision Enhancement of CAR-NK Cells through Non-Viral Engineering and Highly Multiplexed Base Editing

Wang,

Krueger,

Gilkey

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…For instance, antiHER2-CAR NK therapy was investigated in a phase I clinical trial on patients with GBM and revealed higher CD8+ T cell infiltration and the "stabilization of disease" in some of the participants [112]. Recently, we made an attempt to improve NK cell anti-tumor activity by enhancing NK cells via CISH gene knockout [113], based on the fact that the protein encoded by CISH is known to inhibit NK cell susceptibility to IL15 and, consequently, their cytotoxic activity. A promising combinatorial approach is to promote NK and T cell survival via co-transferring them with an IL15/Il15R-expressing oncolytic virus [114].…”

Section: Natural Killer Cellsmentioning

confidence: 99%

Non-Tumor Cells within the Tumor Microenvironment—The “Eminence Grise” of the Glioblastoma Pathogenesis and Potential Targets for Therapy

Bugakova,

Chudakova,

Myzina

et al. 2024

Cells

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Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. GBM has high levels of therapy failure and its prognosis is usually dismal. The phenotypic heterogeneity of the tumor cells, dynamic complexity of non-tumor cell populations within the GBM tumor microenvironment (TME), and their bi-directional cross-talk contribute to the challenges of current therapeutic approaches. Herein, we discuss the etiology of GBM, and describe several major types of non-tumor cells within its TME, their impact on GBM pathogenesis, and molecular mechanisms of such an impact. We also discuss their value as potential therapeutic targets or prognostic biomarkers, with reference to the most recent works on this subject. We conclude that unless all “key player” populations of non-tumor cells within the TME are considered, no breakthrough in developing treatment for GBM can be achieved.

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Enhanced Natural Killers with CISH and B2M Gene Knockouts Reveal Increased Cytotoxicity in Glioblastoma Primary Cultures

Cited by 2 publications

References 21 publications

Precision Enhancement of CAR-NK Cells through Non-Viral Engineering and Highly Multiplexed Base Editing

Precision Enhancement of CAR-NK Cells through Non-Viral Engineering and Highly Multiplexed Base Editing

Non-Tumor Cells within the Tumor Microenvironment—The “Eminence Grise” of the Glioblastoma Pathogenesis and Potential Targets for Therapy

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