Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Stijn De Munter, Juliane L Buhl, Laurenz De Cock, Alexander Van Parys, Willem Daneels, Eva Pascal, Lucas Deseins, Joline Ingels, Glenn Goetgeluk, Hanne Jansen, Lore Billiet, Melissa Pille, Julie Van Duyse, Sarah Bonte, Niels Vandamme, Jo Van Dorpe, Fritz Offner, Georges Leclercq, Tom Taghon, Erik Depla, Jan Tavernier, Tessa Kerre, Jarno Drost, Bart Vandekerckhove
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Abstract

CD70 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy for the treatment of both solid and liquid malignancies. However, the functionality of CD70-specific CAR T cells is modest. We optimized a CD70-specific VHH-based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo, using a diffuse large B-cell lymphoma patient-derived xenograft (PDX) model. Although the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. We determined that fratricide was not causing this loss in efficacy but rather CD70 interaction in cis with the nanoCAR-induced exhaustion. Knocking out CD70 in nanoCAR T cells using CRISPR/Cas9 resulted in dramatically enhanced functionality in the diffuse large B-cell lymphoma PDX model. Through single-cell transcriptomics, we obtained evidence that CD70 knockout CD70-specific nanoCAR T cells were protected from antigen-induced exhaustion. In addition, we demonstrated that wild-type CD70-specific nanoCAR T cells already exhibited signs of exhaustion shortly after production. Their gene signature strongly overlapped with gene signatures of exhausted CAR T cells. Conversely, the gene signature of knockout CD70-specific nanoCAR T cells overlapped with the gene signature of CAR T-cell infusion products leading to complete responses in chronic lymphatic leukemia patients. Our data show that CARs targeting endogenous T-cell antigens negatively affect CAR T-cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target.

敲除 CD70 可使 CD70 特异性 nanoCAR T 细胞从抗原诱导的衰竭中解救出来。
对于治疗实体和液体恶性肿瘤的嵌合抗原受体(CAR)T细胞疗法来说,CD70是一个极具吸引力的靶点。然而,CD70 特异性 CAR T 细胞的功能并不强大。我们优化了一种基于 VHH 的 CD70 特异性 CAR(nanoCAR)。我们在体外使用 CD70 特异性 nanoCAR T 细胞与恶性横纹肌瘤器官组织共培养,在体内使用弥漫大 B 细胞淋巴瘤(DLBCL)患者衍生异种移植(PDX)模型,在临床相关模型中对 nanoCAR 进行了评估。虽然纳米CAR T细胞在类器官共培养中效率很高,但在PDX模型中仅表现出适度的疗效。我们确定,"自相残杀 "并不是导致疗效下降的原因,而是 CD70 与 nanoCAR 的顺式相互作用导致了细胞衰竭。使用 CRISPR/Cas9 基因敲除 nanoCAR T 细胞中的 CD70 后,DLBCL PDX 模型的功能显著增强。通过单细胞转录组学,我们获得了CD70敲除(KO)的CD70特异性纳米CAR T细胞免受抗原诱导的衰竭的证据。此外,我们还证明,WT CD70特异性纳米CAR T细胞在产生后不久就出现了衰竭迹象。它们的基因特征与衰竭的 CAR T 细胞的基因特征高度重叠。另一方面,KO CD70 特异性 nanoCAR T 细胞的基因特征与导致慢性淋巴白血病患者完全应答的 CAR T 细胞输注产物的基因特征重叠。我们的数据表明,以内源性 T 细胞抗原为靶点的 CAR 通过诱导衰竭状态对 CAR T 细胞的功能产生负面影响,而通过敲除特异性靶点可以克服这种影响。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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