肿瘤细胞治疗研究
英文原题：Multimodal C9-66 CAR-T cell immunotherapy improves outcome in preclinical models of pancreatic cancer.
Multimodal C9-66 CAR-T cell immunotherapy improves outcome in preclinical models of pancreatic cancer.
C9-66 CAR-T 细胞经代谢优化与 TME 重编程，代表一种肿瘤特异性、可临床转化的免疫治疗策略，适用于 PDAC 及其他表达 ofCS 的实体瘤。
胰腺导管腺癌（PDAC）因其侵袭性生物学特性和对现有疗法的耐药性，仍是最致命的癌症之一。癌胚硫酸软骨素（ofCS）是一种肿瘤限制性糖胺聚糖，在实体瘤中广泛表达，但在正常成人组织中基本不表达。我们开发了靶向 ofCS 的基于 C9 的嵌合抗原受体（CAR）-T 细胞，以克服抗原特异性差和免疫抑制性肿瘤微环境（TME）的问题。
通过整合CAR设计优化、代谢增强和TME重编程，优化针对PDAC的ofCS靶向C9 CAR-T细胞疗法。
C9 和电荷优化的 C9-66 CAR-T 细胞是使用人源化 ofCS 结合单链抗体片段改造的。在小鼠和患者来源的 PDAC 模型中评估了抗肿瘤效力、功能持久性和代谢适应性。增强策略包括肌苷介导的代谢重编程、Nr5a2 过表达以及使用 GLP-1R 调节、CSF-1R 阻断和程序性细胞死亡蛋白-1 抑制对 TME 进行序贯重塑。
C9 CAR-T 细胞在 PDAC 模型中表现出强效的细胞毒性，延缓了肿瘤进展并延长了生存期。与亲本构建体相比，电荷优化的 C9-66 CAR-T 细胞在体内表现出耗竭减少和活性更持久。肌苷增强了细胞因子产生，促进中枢记忆分化并减轻耗竭，而 Nr5a2 过表达则增加了线粒体呼吸和细胞毒性。序贯 GLP-1R 开关调控联合巨噬细胞和检查点阻断增强了瘤内 CAR-T 细胞活性并延长了生存期。人 C9-66 CAR-T 细胞保留了特异性 ofCS 识别，并在体外和体内裂解了患者来源的 PDAC 细胞。
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers due to its aggressive biology and resistance to existing therapies. Oncofetal chondroitin sulfate (ofCS) is a tumour-restricted glycosaminoglycan broadly expressed across solid cancers but largely absent from normal adult tissues. We developed C9-based chimeric antigen receptor (CAR)-T cells targeting ofCS to overcome poor antigen specificity and the immunosuppressive tumour microenvironment (TME). OBJECTIVE: To optimise ofCS-targeted C9 CAR-T cell therapy for PDAC through integrated CAR design optimisation, metabolic enhancement and TME reprogramming. DESIGN: C9 and charge-optimised C9-66 CAR-T cells were engineered using a humanised ofCS-binding single-chain antibody fragment. Antitumour efficacy, functional durability and metabolic fitness were assessed in murine and patient-derived PDAC models. Enhancement strategies included inosine-mediated metabolic reprogramming, Nr5a2 overexpression and sequential TME remodelling using GLP-1R modulation, CSF-1R blockade and programmed cell death protein-1 inhibition. RESULTS: C9 CAR-T cells exhibited potent cytotoxicity, delayed tumour progression and extended survival in PDAC models. Compared with the parental construct, charge-optimised C9-66 CAR-T cells showed reduced exhaustion and more sustained activity in vivo. Inosine enhanced cytokine production, promoted central-memory differentiation and mitigated exhaustion, whereas Nr5a2 overexpression increased mitochondrial respiration and cytotoxicity. Sequential GLP-1R on-off modulation with macrophage and checkpoint blockade enhanced intratumoural CAR-T cell activity and prolonged survival. Human C9-66 CAR-T cells retained specific ofCS recognition and lysed patient-derived PDAC cells in vitro and in vivo. CONCLUSION: C9-66 CAR-T cells with metabolic optimisation and TME reprogramming represent a tumour-specific and clinically translatable immunotherapeutic strategy for PDAC and other ofCS-expressing solid tumours.
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