دورية أكاديمية

Hypoxia-regulated secretion of IL-12 enhances antitumor activity and safety of CD19 CAR-T cells in the treatment of DLBCL

التفاصيل البيبلوغرافية
العنوان: Hypoxia-regulated secretion of IL-12 enhances antitumor activity and safety of CD19 CAR-T cells in the treatment of DLBCL
المؤلفون: Wenping Zhou, Jinxin Miao, Zhenguo Cheng, Zhimin Wang, Jianyao Wang, Haoran Guo, Pengju Wang, Shuangshuang Lu, Lingling Si, Zhongxian Zhang, Louisa Chard Dunmall, Yanyan Liu, Nicholas R. Lemoine, Yaohe Wang
المصدر: Molecular Therapy: Oncolytics, Vol 30, Iss , Pp 216-226 (2023)
بيانات النشر: Elsevier, 2023.
سنة النشر: 2023
المجموعة: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
مصطلحات موضوعية: CAR-T cells, DLBCL, ODD, IL-12, Syrian hamster model, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: CD19-targeted chimeric antigen receptor-modified T (CD19 CAR-T) cell therapy has been demonstrated as one of the most promising therapeutic strategies for treating B cell malignancies. However, it has shown limited treatment efficacy for diffuse large B cell lymphoma (DLBCL). This is, in part, due to the tumor heterogeneity and the hostile tumor microenvironment. Human interleukin-12 (IL-12), as a potent antitumor cytokine, has delivered encouraging outcomes in preclinical studies of DLBCL. However, potentially lethal toxicity associated with systemic administration precludes its clinical application. Here, an armed CD19 CAR expressing hypoxia-regulated IL-12 was developed (CAR19/hIL12ODD). In this vector, IL-12 secretion was restricted to hypoxic microenvironments within the tumor site by fusion of IL-12 with the oxygen degradation domain (ODD) of HIF1α. In vitro, CAR19/hIL12ODD-T cells could only secrete bioactive IL-12 under hypoxic conditions, accompanied by enhanced proliferation, robust IFN-γ secretion, increased abundance of CD4+, and central memory T cell phenotype. In vivo, adoptive transfer of CAR19/hIL12ODD-T cells significantly enhanced regression of large, established DLBCL xenografts in a novel immunodeficient Syrian hamster model. Notably, this targeted and controlled IL-12 treatment was without toxicity in this model. Taken together, our results suggest that armed CD19 CARs with hypoxia-controlled IL-12 (CAR19/hIL12ODD) might be a promising and safer approach for treating DLBCL.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2372-7705
Relation: http://www.sciencedirect.com/science/article/pii/S2372770523000608; https://doaj.org/toc/2372-7705
DOI: 10.1016/j.omto.2023.08.009
URL الوصول: https://doaj.org/article/9d62516814ab4d5fb98012e3b88a0c17
رقم الأكسشن: edsdoj.9d62516814ab4d5fb98012e3b88a0c17
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:23727705
DOI:10.1016/j.omto.2023.08.009