Hypoxia-regulated secretion of IL-12 enhances antitumor activity and safety of CD19 CAR-T cells in the treatment of DLBCL.
Hypoxia-regulated secretion of IL-12 enhances antitumor activity and safety of CD19 CAR-T cells in the treatment of DLBCL.
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DOI：
10.1016/j.omto.2023.08.009
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发表时间：
2023-09-21
期刊：
影响因子：
--
通讯作者：
Wang, Yaohe
中科院分区：
文献类型：
--
作者：
Zhou, Wenping;Miao, Jinxin;Cheng, Zhenguo;Wang, Zhimin;Wang, Jianyao;Guo, Haoran;Wang, Pengju;Lu, Shuangshuang;Si, Lingling;Zhang, Zhongxian;Dunmall, Louisa Chard;Liu, Yanyan;Lemoine, Nicholas R.;Wang, Yaohe
CD 19靶向嵌合抗原受体修饰的T（CD 19 CAR-T）细胞疗法已被证明是治疗B细胞恶性肿瘤最有前景的治疗策略之一。然而，它对弥漫性大B细胞淋巴瘤（DLBCL）的治疗效果有限。这部分是由于肿瘤的异质性和不利的肿瘤微环境。人白细胞介素-12（IL-12）作为一种有效的抗肿瘤细胞因子，在DLBCL的临床前研究中取得了令人鼓舞的成果。然而，与全身给药相关的潜在致死毒性排除了其临床应用。在此，开发了表达低氧调节的IL-12的武装⑶ 19 CAR（CAR 19/hIL 12 ODD）。在该载体中，通过将IL-12与HIF 1 α的氧降解结构域（ODD）融合，将IL-12分泌限制在肿瘤部位内的缺氧微环境中。在体外，CAR 19/hIL 12 ODD-T细胞在缺氧条件下仅能分泌生物活性IL-12，伴随着增殖增强、IFN-γ分泌稳健、CD 4+丰度增加和中枢记忆T细胞表型。在体内，CAR 19/hIL 12 ODD-T细胞的过继转移显著增强了新型免疫缺陷叙利亚仓鼠模型中大的已建立DLBCL异种移植物的消退。值得注意的是，这种靶向和受控的IL-12治疗在该模型中没有毒性。综上所述，我们的结果表明，用低氧控制的IL-12武装CD 19汽车（CAR 19/hIL 12 ODD）可能是治疗DLBCL的一种有前景和更安全的方法。开发了表达缺氧调节的IL-12的CD 19 CAR（CAR 19/hIL 12 ODD），其中IL-12的表达通过HIF 1 α的融合ODD结构域被缺氧调节。这种新型CAR限制了呈现缺氧微环境的肿瘤内IL-12的表达，并且可以增强CD 19 CAR-T细胞的抗肿瘤活性而没有全身毒性。
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. A CD19 CAR expressing hypoxia-regulated IL-12 was developed (CAR19/hIL12ODD), in which IL-12 expression is regulated by the hypoxia through fusion ODD domain of HIF1α. This novel CAR restricts the expression of IL-12 within tumors presenting hypoxic microenvironment and could boost the antitumor activity of CD19 CAR-T cells without systemic toxicity.
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影响因子：
20.3
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
通讯作者：
Jensen, Michael C.
DOI：
10.1097/cji.0b013e3181ac6138
发表时间：
2009-09
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Kochenderfer JN;Feldman SA;Zhao Y;Xu H;Black MA;Morgan RA;Wilson WH;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
4.4
作者：
Budda, Scott A.;Girton, Alanson;Zenewicz, Lauren A.
通讯作者：
Zenewicz, Lauren A.
影响因子：
7.2
作者：
Koneru, Mythili;Purdon, Terence J.;Brentjens, Renier J.
通讯作者：
Brentjens, Renier J.