bims-limsir 2023-07-23 papers

Blood Adv. 2023 Jul 19. pii: bloodadvances.2023010643. [Epub ahead of print]

Small interfering RNA-mediated allele-selective silencing of von Willebrand factor in vitro and in vivo.

Yvonne K Jongejan, Elisa Schrader Echeverri, Richard J Dirven, Kalina Paunovska, Noa A Linthorst, Annika de Jong, Johannes C Wellershoff, Kim Daniëlle van der Gouw, Bart J M van Vlijmen, James E Dahlman, Jeroen C J Eikenboom.

An imbalance in von Willebrand factor (VWF) may either lead to bleeding (von Willebrand disease, VWD) or thrombosis. Both disorders have shortcomings in the currently available treatments. VWF itself could be a potential therapeutic target because of its role in both bleeding and thrombosis. Inhibiting VWF gene expression through allele-selective silencing of VWF with small interfering RNAs (siRNAs) could be a personalized approach to specifically inhibit mutant VWF in VWD or to normalize increased VWF levels in thrombotic disorders without complete VWF knockdown. Therefore, we investigated a method to allele-selectively silence the VWF gene in mice as a therapeutic strategy. Fourteen candidate siRNAs targeting murine Vwf of either the C57BL/6J (B6) or the 129S1/SvImJ (129S) strain were tested in vitro in cells expressing B6- and 129S-Vwf on inhibitory effect and allele-selective potential. Together with a non-selective siVwf, two lead candidate siRNAs, siVwf.B6 and siVwf.129S, were further tested in vivo in B6 and 129S mice. Efficient endothelial siRNA delivery was achieved by siRNA encapsulation into 7C1 oligomeric lipid nanoparticles. Treatment with the non-selective siVwf resulted in a dose-dependent inhibition up to 80% of both lung mRNA and plasma VWF protein in both mouse strains. In contrast, the allele-selective siVwf.B6 and siVwf.129S were shown to be effective in and selective solely for their corresponding mouse strain. To conclude, we showed efficient endothelial delivery of siRNAs that are highly effective in allele-selective inhibition of Vwf in mice, which constitute an in vivo proof of principle of allele-selective VWF-silencing as a therapeutic approach.

DOI: https://doi.org/10.1182/bloodadvances.2023010643

Hum Cell. 2023 Jul 21.

Chimeric antigen receptor-natural killer cells: a promising sword against insidious tumor cells.

Tahereh Hojjatipour, Zahra Sharifzadeh, Amirhosein Maali, Mehdi Azad.

Natural killer (NK) cells are a critical component of innate immunity, particularly in initial cancer recognition and inhibition of additional tumor growth or metastasis propagation. NK cells recognize transformed cells without prior sensitization via stimulatory receptors and rapidly eradicate them. However, the protective tumor microenvironment facilitates tumor escaping via induction of an exhaustion state in immune cells, including NK cells. Hence, genetic manipulation of NK cells for specific identification of tumor-associated antigens or a more robust response against tumor cells is a promising strategy for NK cells' tumoricidal augmentation. Regarding the remarkable achievement of engineered CAR-T cells in treating hematologic malignancies, there is evolving interest in CAR-NK cell recruitment in cancer immunotherapy. Innate functionality of NK cells, higher safety, superior in vivo maintenance, and the off-the-shelf potential move CAR-NK-based therapy superior to CAR-T cells treatment. In this review, we have comprehensively discussed the recent genetic manipulations of CAR-NK cell manufacturing regarding different domains of CAR constructs and their following delivery systems into diverse sources of NK cells. Then highlight the preclinical and clinical investigations of CAR-NK cells and examine the current challenges and prospects as an optimistic remedy in cancer immunotherapy.

Keywords: Adoptive cellular therapy; CAR-NK cells; Cancer immunotherapy; Chimeric antigen receptors; NK cell

DOI: https://doi.org/10.1007/s13577-023-00948-w

Front Immunol. 2023 ;14 1213716

Recent advances and future perspectives of CAR-T cell therapy in head and neck cancer.

Chunmei Hu, Min Liu, Yutao Li, Yi Zhao, Amit Sharma, Haotian Liu, Ingo G H Schmidt-Wolf.

Head and neck cancer (HNC) ranks as the sixth most prevalent type of cancer globally and accounts for about 4% of all types of cancer. Among all HNC, most are head and neck squamous cell carcinoma (HNSCC) with clinical therapies that include surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy, and multimodal treatments. In recent years, chimeric antigen receptor (CAR)-T cell immunotherapy has significantly transformed the therapeutic approaches for leukemia and lymphoma and has garnered increased attention as a potential treatment for a wide range of cancers. However, CAR-T immunotherapy in solid tumors, especially HNSCCs, lags significantly behind due to the paucity of tumor-specific antigens, high levels of tumor heterogeneity, immunosuppressive tumor microenvironment, the risk of treatment-related toxicities and off-target adverse events in HNSCCs. The objective of this review is to explore the advancement of CAR-T cell therapy in the treatment of HNSCCs. We aim to outline the targeted antigens in HNSCCs, highlight the challenges and potential solutions, and discuss the relevant combination therapies. Our review presents a comprehensive overview of the recent developments in CAR-T cell therapy for HNSCCs, and provides valuable insights into future research avenues.

Keywords: CAR-T cell therapy; head and neck cancer; head and neck squamous cell carcinoma; immune checkpoint inhibitors; immunotherapy

DOI: https://doi.org/10.3389/fimmu.2023.1213716