Engineering T cells with hypoxia-inducible chimeric antigen receptor (HiCAR) for selective tumor killing
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LETTER TO THE EDITOR
Open Access
Engineering T cells with hypoxia-inducible chimeric antigen receptor (HiCAR) for selective tumor killing Qibin Liao†, Huan He†, Yunyu Mao, Xiangqing Ding, Xiaoyan Zhang* and Jianqing Xu*
Abstract Chimeric antigen receptor-modified T cells (CAR-T cells) have shown good effects in the treatment of hematologic cancers; however, they may cause on-target off-tumor toxicity because of minimal expression of tumor-associated antigens (TAAs) on normal tissues, particularly in the context of treating solid tumors. Hypoxia is a common hallmark of solid tumors because of the Warburg effect. To minimize side effects, we designed a hypoxia-inducible CAR (HiCAR), which is driven by a hypoxia response element (HRE), and consists of a conventional CAR and an oxygen-dependent degradation domain (ODD) that is actively degraded under normoxia but stabilized under hypoxia. HiCAR-T cells showed enhanced cytotoxicity against tumor cells under hypoxia compared to normoxia in vitro and antitumor efficacy comparable to that of conventional CAR-T cells in vivo. Overall, our study demonstrates the potential of the HiCAR for improving the safety of CAR-T cells to promote the clinical application of CAR-T immunotherapy. Keywords: On-target off-tumor, Hypoxia, Hypoxia-inducible CAR, Hypoxia response element To the Editor, Chimeric antigen receptor-modified T cells (CAR-T cells) have shown strong antitumor activity against hematologic cancers [1, 2], which has led to safety concerns regarding on-target off-tumor toxicity, particularly in normal tissues with low expression levels of tumorassociated antigens (TAAs) that are recognized by CART cells [3, 4]. Recent years have seen the emergence of many strategies to spatiotemporally control CAR-T cell activities through regulating antigen recognition [5, 6], but the application of tumor environmental signals (e.g., acidosis and hypoxia) may represent an attractive strategy to control CAR-T cells. A previous study showed that oxygen-sensitive multichain CAR-T cells are responsive to hypoxia [7], while a simple single-chain * Correspondence: [email protected]; [email protected] Qibin Liao and Huan He are Co-first authors Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
hypoxia-inducible CAR-T cells (HiCAR-T cells) could respond to hypoxia within solid tumors is elusive. We aimed to develop a CAR design that require both antigen recognition and hypoxia sensing to generate optimal T cell activity, thereby reducing on-target off-tumor toxicity. This design, founded on the oxygen-dependent degradation domain (ODD), might be particularly useful for targeting common antigens shared between normal and neoplastic tissues. We first compared the hypoxiasensitivity of four ODDs, three from hypoxia inducible factor-1α (HIF-1α) and one from activating transcription factor-4 (ATF4) [8], using an mCherry-based reporter system (Additional file 1: Figure S1a). Among the four ODDs, the large HIF-1α ODD confer
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