Off-the-shelf CAR T cells need to reliably escape allogeneic immune responses to become universal medicines. The primary T cell product SC291 was engineered with a CD19 CAR, T cell receptor alpha constant (TRAC) knockout, and the hypoimmune (HIP) edits of HLA depletion and CD47 overexpression. Here, we report exploratory immune analyses from the ARDENT (NCT05878184) and GLEAM (NCT06294236) trials with HIP-edited CD19 CAR T cells. Although there was an alloimmune response against HLA-replete subpopulations of SC291, we observed no de novo immune response against fully edited HIP CAR T cells in all patients, irrespective of the dose or the patient's disease. The lack of antibodies against the HLA-replete CAR T cells was identified as a marker for deep tissue CD19 cell depletion, and all patients without such antibodies for 60 days showed concomitant B cell depletion in peripheral blood. The immune data presented support the reliability of the HIP concept to evade allorejection.

2025-07-01·iScience

Hypoimmune CD19 CAR T cells treat allogeneic mice with features of spontaneous systemic lupus erythematosus

Article

作者: Friera, Annabelle ; Caruso, Carolin B ; Wang, Chenyan ; Olroyd, Ari G ; Connolly, Andrew J ; White, Kathy ; Schrepfer, Sonja ; Hu, Xiaomeng ; Deuse, Tobias

Hypoimmune (HIP) MHC class I- and II-deficient and CD47-overexpressing CD19 CAR T cells were generated and tested in an allogeneic NZB/W mouse model of spontaneous systemic lupus erythematosus with established disease. HIP CAR T cells showed persistent engraftment, achieved lasting deep tissue B cell depletion, diminished antibody levels and systemic pro-inflammatory cytokine levels, mitigated proteinuria and glucosuria, alleviated structural kidney injury, and improved survival after 21 weeks. HIP CAR T cells did not induce any immune activation in this fully allogeneic model and thus completely escaped allorejection. In contrast, MHC-replete, non-HIP-edited wild-type (WT) CD19 CAR T cells induced a strong adaptive immune response and vanished quickly without inducing meaningful B cell depletion and without improving disease markers or survival. Conditioning of NZB/W mice with irradiation did not enhance the HIP CAR T cell efficacy and might hint at their potency for autoimmune patients without prior lymphodepletion.

2020-12-01·Biomarker research

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

Letter

作者: Ding, Xiangqing ; Liao, Qibin ; He, Huan ; Zhang, Xiaoyan ; Mao, Yunyu ; Xu, Jianqing

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.

100 项与 HiCAR-T 相关的药物交易

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