ADI-270:一种装甲异体γ δ T细胞疗法,设计用于靶向表达cd70的实体和血液恶性肿瘤。

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Kevin P Nishimoto, Gauri Lamture, Yvan Chanthery, Alexander G Teague, Yogendra Verma, Melinda Au, Morgan Smith-Boeck, Michael Salum, Pranav Murthy, Smitha R Y Gundurao, Ramandeep Kaur, Jie Zhang, Aruna Azameera, Jonathan T S Wong, Elizabeth B Speltz, Katherine M Wang, Amy Doan, Jyothi Sethuraman, Dishant Bhatwala, Ana Giner-Rubio, Pavan Puligujja, Helen Budworth, Christopher J Rold, Swapna Panuganti, Aya Jakobovits, Marissa Herrman, Arun Bhat, Shon Green, Blake T Aftab
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引用次数: 0

摘要

背景:肿瘤微环境(TME)提出了限制传统CAR-T细胞治疗效果的挑战。归巢屏障、免疫抑制因子和靶抗原异质性可损害TME内CAR-T细胞的功能活性。备选策略已经考虑纳入使用γδ (γδ) T细胞作为CAR-T细胞方法,以潜在地克服这些局限性。γδ T细胞具有先天免疫和适应性免疫,促进广泛的肿瘤识别,并且它们的自然组织倾向可能允许更有效的肿瘤浸润。本文报道了ADI-270的临床前特性,ADI-270是一种针对CD70+癌症的同种异体γδ CAR- t细胞产品,采用基于天然CD27受体的第三代CAR进行工程化。ADI-270也是双装甲,以减轻TGFβ的免疫抑制作用,并减少异体排斥反应的可能性。方法:从健康供体人外周血细胞中扩增表达抗cd70 CAR和显性阴性TGFβ受体II (dnTGFβRII)的Vδ1 T细胞。ADI-270的表型和功能特性通过体外细胞培养试验和体内肿瘤异种移植模型进行评估。结果:与基于scfv的抗cd70 CAR - αβ T细胞相比,ADI-270对一系列癌细胞表现出高水平的体外细胞毒性,并显示出有利的炎症细胞因子谱。尽管在多种实体和血液肿瘤细胞模型中观察到低CD70表达,但细胞毒性仍然有效。当用dnTGFβRII装甲时,ADI-270对tgf β介导的T细胞效应活性抑制表现出功能弹性。此外,在体外实验中,有效且敏感的靶向cd70的掺入减少了T细胞介导的对ADI-270的同种异体反应性杀伤,没有证据表明存在杀兄弟性。最后,ADI-270在异种移植小鼠模型中显示出强大的肿瘤趋向性和对原发性和继发性肿瘤的控制。结论:这些结果证明了ADI-270的强大效力和能力,可以将抗肿瘤活性扩展到具有异质抗原表达的癌症。纳入ADI-270的功能性装甲提供了一种机制来克服TME内效能降低和持久性的限制。ADI-270在复发/难治性透明细胞肾细胞癌的初步临床评估中具有靶向多种CD70+癌症的潜力。试验注册号:NCT06480565。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ADI-270: an armored allogeneic gamma delta T cell therapy designed to target CD70-expressing solid and hematologic malignancies.

Background: The tumor microenvironment (TME) poses challenges that limit the efficacy of conventional CAR-T cell therapies. Homing barriers, immunosuppressive factors, and target antigen heterogeneity can impair CAR-T cell functional activity within the TME. Alternative strategies have contemplated incorporating the use of gamma delta (γδ) T cells as a CAR-T cell approach to potentially overcome these limitations. γδ T cells possess both innate and adaptive immunity to facilitate broad tumor recognition, and their natural propensity for tissue tropism may allow for more effective tumor infiltration. Reported here is the preclinical characterization of ADI-270, an allogeneic γδ CAR-T cell product targeting CD70+ cancers, engineered with a third-generation CAR based on the natural CD27 receptor. ADI-270 is also double-armored to mitigate the immunosuppressive effects of TGFβ and reduce the potential for allogeneic rejection.

Methods: Vδ1 T cells engineered to express an anti-CD70 CAR and dominant negative TGFβ receptor II (dnTGFβRII) were expanded from healthy donor human PBMCs. The phenotype and functional characterization of ADI-270 were assessed with in vitro cell culture assays and in vivo tumor xenograft models.

Results: ADI-270 exhibited high levels of in vitro cytotoxicity against a panel of cancer cell lines and displayed a favorable inflammatory cytokine profile compared with reference scFv-based anti-CD70 CAR αβ T cells. Cytotoxicity remained potent despite low CD70 expression observed in multiple solid and hematologic tumor cell models. When armored with dnTGFβRII, ADI-270 exhibited functional resilience to TGFβ-mediated inhibition of T cell effector activity. In addition, the incorporation of potent and sensitive CD70-targeting decreased T cell-mediated alloreactive killing against ADI-270 in vitro without evidence of fratricide. Finally, ADI-270 displayed robust tumor tropism and control of primary and secondary tumor challenges in xenograft mouse models.

Conclusions: These results demonstrate the robust potency and capacity of ADI-270 to extend antitumor activity to cancers with heterogeneous antigen expression. The functional armoring incorporated into ADI-270 provides a mechanism to overcome the limitations of reduced efficacy and persistence within the TME. ADI-270 has the potential to target multiple CD70+ cancers with initial clinical evaluation proceeding in relapsed/refractory clear cell renal cell carcinoma.

Trial registration number: NCT06480565.

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来源期刊
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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