Engineering c-Met-CAR NK-92 cells as a promising therapeutic candidate for lung adenocarcinoma

Peng, Yan; Zhang, Wenqing; Chen, Yufeng; Zhang, Louqian; Shen, Huan; Wang, Zheyue; Tian, Shuning; Yang, Xiaohui; Cui, Daixun; He, Yongtao; Chang, Xinxia; Feng, Zhenqing; Tang, Qi; Yuan, Man

doi:10.1016/j.phrs.2023.106656

Cited by 25 publications

(11 citation statements)

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“…Engineered CAR-NK cells targeting CD44, a marker abundantly expressed by ovarian cancer cells, showed potent cytotoxicity against CD44-positive ovarian cancer cells [20]. In lung adenocarcinoma, CAR-NK92 cells targeting mesenchymal-epithelial transition factor (C-Met) showed promising results in lung xenograft models [21]. These experiments provide insight into the future of utilizing engineered CAR-NK cells as a solid tumor cancer therapeutic.…”

Section: Car-nk Cells Pick Up Where Car-t Cells Left Offmentioning

confidence: 89%

“…Although NK cells have immense potential and have shown various advantages over T-cell therapy, there are disadvantages to NK cell therapy that need to be discussed: (i) difficult to modify, especially with frozen cells; (ii) if the cells are derived from iPSCs or cord blood, they often express low levels of CD16 which is a sign of decreased antibody-dependent cellular cytotoxicity [22,23]; (iii) short in vivo lifespan [21]; (iv) low viability after being defrosted from cryopreservation [21]; (v) NK cell exhaustion [21]; and (vi) high chance of inhibition by inhibitory receptors [21]. These are the hurdles that current investigators are attempting to jump.…”

Section: Car-nk Cells Pick Up Where Car-t Cells Left Offmentioning

confidence: 99%

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Application of natural killer immunotherapy in blood cancers and solid tumors

Sayegh

2023

Current Opinion in Oncology

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Purpose of review Natural killer (NK) cells are innate lymphoid cells characterized by their ability to attack aberrant and cancerous cells. In contrast to the activation of T-cells, NK cell activation is controlled by the interaction of NK cell receptors and their target cells in a manner independent of antigen organization. Due to NK cells’ broad array of activation cues, they have gained great attention as a potential therapeutic agent in cancer immunotherapy. Recent findings Ex vivo activation, expansion, and genetic modifications, such as the addition of a chimeric antigen receptor (CAR), will allow the next generation of NK cells to enhance cytotoxicity, promote survival, and create “off-the-shelf” products. In addition to these that are poised to greatly enhance their clinical activity, the inherent lack of potential for causing graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) suggest that CAR NK cells have the potential to be complementary to CAR-T cells as a component of therapeutic strategies for cancer. Summary In this review, we will provide a general understanding of NK cell biology, CAR-NK cell advantages over CAR-T cell therapy, barriers to making NK cell immunotherapy viable, and current NK cell clinical trials for hematological malignancies and solid tumors. The next generation of NK cells has potential to change the circumstances guiding present cancer immunotherapies.

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Section: Car-nk Cells Pick Up Where Car-t Cells Left Offmentioning

confidence: 89%

Section: Car-nk Cells Pick Up Where Car-t Cells Left Offmentioning

confidence: 99%

Application of natural killer immunotherapy in blood cancers and solid tumors

Sayegh

2023

Current Opinion in Oncology

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“…Immunohistochemistry (IHC) analysis supported these findings, revealing increased CD56, perforin, and granzyme B protein expression, indicating CCN4-induced tumor necrosis and upregulated NK cell infiltration. Collectively, these findings suggest that c-Met CAR NK cells hold the potential to effectively eliminate tumors and extend the survival of tumor-bearing mice ( 41 ).…”

Section: Car-nk and Non-hematological Solid Tumorsmentioning

confidence: 95%

“…These are capable of recognizing and targeting tumor cells expressing specific antigens through their chimeric antigen receptors (CARs). Upon engagement with these target cells, CAR-NK cells can trigger both necrotic and apoptotic pathways within the tumor cells, resulting in their destruction ( 41 ) as shown in Figure 2 . This dual mechanism of action enables CAR NK cells to effectively eliminate cancer cells while minimizing the potential for immune evasion and resistance mechanisms employed by tumors.…”

Section: Chimeric Antigen Receptor-nk Cellsmentioning

confidence: 99%

Antitumor activity of genetically engineered NK-cells in non-hematological solid tumor: a comprehensive review

Dash,

Sonowal,

Dhaka

et al. 2024

Front. Immunol.

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Recent advancements in genetic engineering have made it possible to modify Natural Killer (NK) cells to enhance their ability to fight against various cancers, including solid tumors. This comprehensive overview discusses the current status of genetically engineered chimeric antigen receptor NK-cell therapies and their potential for treating solid tumors. We explore the inherent characteristics of NK cells and their role in immune regulation and tumor surveillance. Moreover, we examine the strategies used to genetically engineer NK cells in terms of efficacy, safety profile, and potential clinical applications. Our investigation suggests CAR-NK cells can effectively target and regress non-hematological malignancies, demonstrating enhanced antitumor efficacy. This implies excellent promise for treating tumors using genetically modified NK cells. Notably, NK cells exhibit low graft versus host disease (GvHD) potential and rarely induce significant toxicities, making them an ideal platform for CAR engineering. The adoptive transfer of allogeneic NK cells into patients further emphasizes the versatility of NK cells for various applications. We also address challenges and limitations associated with the clinical translation of genetically engineered NK-cell therapies, such as off-target effects, immune escape mechanisms, and manufacturing scalability. We provide strategies to overcome these obstacles through combination therapies and delivery optimization. Overall, we believe this review contributes to advancing NK-cell-based immunotherapy as a promising approach for cancer treatment by elucidating the underlying mechanisms, evaluating preclinical and clinical evidence, and addressing remaining challenges.

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“…In addition to surgery, treatment options for LUAD include chemotherapy, molecular targeting, and immunotherapy. Approximately 30% of LUAD cases possess molecular targets that can be addressed with targeted drugs (Peng et al 2023 ). For patients with advanced LUAD who are not eligible for molecularly targeted treatment, immune checkpoint inhibitors (ICIs) are administered, resulting in a substantial increase in 5-year survival rates from under 5% during chemotherapy to around 30% (Reck et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of co-expressed genes with TDP-43: prognostic and therapeutic potential in lung adenocarcinoma

Zhang,

Lin,

Yahaya

2024

J Cancer Res Clin Oncol

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Background Transactivating DNA-binding protein 43 (TDP-43) is intimately associated with tumorigenesis and progression by regulating mRNA splicing, transport, stability, and non-coding RNA molecules. The exact role of TDP-43 in lung adenocarcinoma (LUAD) has not yet been fully elucidated, despite extensive research on its function in various cancer types. An imperative aspect of comprehending the underlying biological characteristics associated with TDP-43 involves investigating the genes that are co-expressed with this protein. This study assesses the prognostic significance of these co-expressed genes in LUAD and subsequently explores potential therapeutic strategies based on these findings. Methods Transcriptomic and clinical data pertaining to LUAD were retrieved from open-access databases to establish an association between mRNA expression profiles and the presence of TDP-43. A risk-prognosis model was developed to compare patient survival rates across various groups, and its accuracy was also assessed. Additionally, differences in tumor stemness, mutational profiles, tumor microenvironment (TME) characteristics, immune checkpoints, and immune cell infiltration were analyzed in the different groups. Moreover, the study entailed predicting the potential response to immunotherapy as well as the sensitivity to commonly employed chemotherapeutic agents and targeted drugs for each distinct group. Results The TDP-43 Co-expressed Gene Risk Score (TCGRS) model was constructed utilizing four genes: Kinesin Family Member 20A (KIF20A), WD Repeat Domain 4 (WDR4), Proline Rich 11 (PRR11), and Glia Maturation Factor Gamma (GMFG). The value of this model in predicting LUAD patient survival is effectively illustrated by both the Kaplan–Meier (K–M) survival curve and the area under the receiver operating characteristic curve (AUC-ROC). The Gene Set Enrichment Analysis (GSEA) revealed that the high TCGRS group was primarily enriched in biological pathways and functions linked to DNA replication and cell cycle; the low TCGRS group showed primary enrichment in immune-related pathways and functions. The high and low TCGRS groups showed differences in tumor stemness, mutational burden, TME, immune infiltration level, and immune checkpoints. The predictions analysis of immunotherapy indicates that the Tumor Immune Dysfunction and Exclusion (TIDE) score (p < 0.001) and non-response rate (74% vs. 51%, p < 0.001) in the high TCGRS group are higher than those in the low TCGRS group. The Immune Phenotype Score (IPS) in the high TCGRS group is lower than in the low TCGRS group (p < 0.001). The drug sensitivity analysis revealed that the half-maximal inhibitory concentration (IC50) values for cisplatin, docetaxel, doxorubicin, etoposide, gemcitabine, paclitaxel, vincristine, erlotinib, and gefitinib (all p < 0.01) in the high TCGRS group are lower than those in the low TCGRS group. Conclusions The TCGRS derived from the model exhibits a reliable biomarker for evaluating both prognosis and treatment effectiveness among patients with LUAD. This study is anticipated to offer valuable insights into developing effective treatment strategies for this patient population. It is believed that this study is anticipated to contribute significantly to clinical diagnostics, the development of therapeutic drugs, and the enhancement of patient care.

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Engineering c-Met-CAR NK-92 cells as a promising therapeutic candidate for lung adenocarcinoma

Cited by 25 publications

References 50 publications

Application of natural killer immunotherapy in blood cancers and solid tumors

Application of natural killer immunotherapy in blood cancers and solid tumors

Antitumor activity of genetically engineered NK-cells in non-hematological solid tumor: a comprehensive review

Comprehensive analysis of co-expressed genes with TDP-43: prognostic and therapeutic potential in lung adenocarcinoma

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