Engineering T cells with hypoxia-inducible chimeric antigen receptor (HiCAR) for selective tumor killing

Liao, Qiuyan; He, Hong; Mao, Yunyu; Ding, Xiangqing; Zhang, Xiaoyan; Xu, Jianqing

doi:10.1186/s40364-020-00238-9

Cited by 24 publications

(22 citation statements)

References 10 publications

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“…Juillerat et al was the first to fuse the HIF-1α ODD to the CAR scaffold, termed HIF-CAR, and demonstrate a CAR T-cell only responsive in hypoxic environments [ 276 ]. Recently, two other hypoxia-sensing CARs, termed HiCAR and HypoxiCAR, have been developed, and both utilize the HIF-1α ODD [ 277 , 278 ]. In addition, HiCAR and HypoxiCAR incorporate single or consecutive HREs upstream of their promoter to induce CAR expression in hypoxic conditions, leading to dual hypoxia sensing, and demonstrating the versatility and potential for immunotherapy.…”

Section: Future Perspectivesmentioning

confidence: 99%

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

Davis

Recktenwald

Hutt

et al. 2022

Cancers

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Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions.

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Section: Future Perspectivesmentioning

confidence: 99%

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

Davis

Recktenwald

Hutt

et al. 2022

Cancers

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“…The second generation of this approach was developed as a dual oxygen-sensing method (Figure 11A). [118][119][120] This was achieved by fusing an ODD to the CAR as well as modifying the CAR's promoter to include hypoxia-responsive elements (HREs), which allowed HIF1α-mediated transcription of the CAR. An oxygen-sensing switch provides stringent hypoxia-dependent regulation of a CAR (Figure 11B, C).…”

Section: Hypoxia-sensing Carsmentioning

confidence: 99%

Emerging approaches for preventing cytokine release syndrome in CAR-T cell therapy

et al. 2022

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“…To make this transcriptional system oxygen-sensing, the C-terminal of ZFP-VP64 was fused with ODD 25 to generate a hypoxia-regulated activator ZPO. The ZPO was further put in trans upstream to five copies of HRE 39 followed by cytomegalovirus minimal promoter (CMV mp) to generate ZPO-HRE.…”

Section: Transactivators Plasmidsmentioning

confidence: 99%

“…22 23 Hypoxiaregulated CAR-T cells are proposed to increase tumor selectivity and reduce on-target off-tumor toxicity to normal tissues, 22 23 and would be applicable to a wide range of tumors. HIF-CAR 24 and HiCAR 25 have been constructed by incorporating HRE and/or ODD into conventional CAR structure. Although these CAR-T cells exhibited well oxygen sensitivity, we observed residual CAR expression and cytolytic activity under normoxia but less-than-desirable CAR expression under hypoxia.…”

Section: Introductionmentioning

confidence: 99%

“…Although these CAR-T cells exhibited well oxygen sensitivity, we observed residual CAR expression and cytolytic activity under normoxia but less-than-desirable CAR expression under hypoxia. 24 25 Besides, compared with many hypoxia-activated prodrugs entering clinical trials, 26 up to now, no hypoxia-regulated CAR-T cells have been progressed into clinical trial, suggesting further improvement is required.…”

Section: Introductionmentioning

confidence: 99%

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Conditioned CAR-T cells by hypoxia-inducible transcription amplification (HiTA) system significantly enhances systemic safety and retains antitumor efficacy

Liao

Zhao

et al. 2021

J Immunother Cancer

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BackgroundHypoxia is a striking feature of most solid tumors and could be used to discriminate tumors from normoxic tissues. Therefore, the design of hypoxia-conditioned Chimeric Antigen Receptor (CAR) T cells is a promising strategy to reduce on-target off-tumor toxicity in adoptive cell therapy. However, existing hypoxia-conditioned CAR-T designs have been only partially successful in enhancing safety profile but accompanied with reduced cytotoxic efficacy. Our goal is to further improve safety profile with retained excellent antitumor efficacy.MethodsIn this study, we designed and constructed a hypoxia-inducible transcription amplification system (HiTA-system) to control the expression of CAR in T (HiTA-CAR-T) cells. CAR expression was determined by Flow cytometry, and the activation and cytotoxicity of HiTA-CAR-T cells in vitro were evaluated in response to antigenic stimulations under hypoxic or normoxic conditions. The safety of HiTA-CAR-T cells was profiled in a mouse model for its on-target toxicity to normal liver and other tissues, and antitumor efficacy in vivo was monitored in murine xenograft models.ResultsOur results showed that HiTA-CAR-T cells are highly restricted to hypoxia for their CAR expression, activation and cytotoxicity to tumor cells in vitro. In a mouse model in vivo, HiTA-CAR-T cells targeting Her2 antigen showed undetectable CAR expression in all different normoxic tissues including human Her2-expresing liver, accordingly, no liver and systemic toxicity were observed; In contrast, regular CAR-T cells targeting Her2 displayed significant toxicity on human Her2-expression liver. Importantly, HiTA-CAR-T cells were able to achieve signiﬁcant tumor suppression in murine xenograft models.ConclusionOur HiTA system showed a remarkable improvement in hypoxia-restricted transgene expression in comparison with currently available systems. HiTA-CAR-T cells presented significant antitumor activities in absence of any significant liver or systemic toxicity in vivo. This approach could be also applied to design CAR-T cell targeting other tumor antigens.

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Engineering T cells with hypoxia-inducible chimeric antigen receptor (HiCAR) for selective tumor killing

Cited by 24 publications

References 10 publications

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

Emerging approaches for preventing cytokine release syndrome in CAR-T cell therapy

Conditioned CAR-T cells by hypoxia-inducible transcription amplification (HiTA) system significantly enhances systemic safety and retains antitumor efficacy

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