Sustained Intratumoral Administration of Agonist CD40 Antibody Overcomes Immunosuppressive Tumor Microenvironment in Pancreatic Cancer.
Sustained Intratumoral Administration of Agonist CD40 Antibody Overcomes Immunosuppressive Tumor Microenvironment in Pancreatic Cancer.
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DOI：
10.1002/advs.202206873
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发表时间：
2023-03
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激动剂CD40单克隆抗体（mAb）是一种很有前途的肿瘤冷-热免疫微环境（TIME）转化的免疫治疗剂。胰腺导管腺癌（PDAC）是一种侵袭性和致死性癌症，被称为免疫沙漠，因此迫切需要更有效的治疗。常规的全身治疗不能有效穿透肿瘤间质。本研究表明，在小鼠模型中，通过纳米流体药物洗脱种子（NDES）持续低剂量给药CD40 mAb可以调节时间以减轻肿瘤负荷。NDES以比全身治疗低四倍的剂量实现肿瘤缩小，同时避免了治疗相关的不良事件。此外，体外反应显示，肿瘤内治疗产生生长抑制远端未经治疗的肿瘤。总的来说，NDES被认为是一种可行的方法，以微创和有效的方式穿透PDAC免疫屏障，以实现转化治疗的总体目标。纳米流体药物洗脱种子（NDES）可以实现长期的肿瘤内免疫治疗。持续低剂量激动剂CD40单克隆抗体通过NDES递送，在免疫抑制的胰腺肿瘤微环境中有效触发抗肿瘤免疫应答，无治疗相关不良事件。总的来说，NDES提供了一种有效的低剂量肿瘤靶向药物递送方法，可提高治疗疗效和生存率。
Agonist CD40 monoclonal antibodies (mAb) is a promising immunotherapeutic agent for cold‐to‐hot tumor immune microenvironment (TIME) conversion. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer known as an immune desert, and therefore urgently needs more effective treatment. Conventional systemic treatment fails to effectively penetrate the characteristic dense tumor stroma. Here, it is shown that sustained low‐dose intratumoral delivery of CD40 mAb via the nanofluidic drug‐eluting seed (NDES) can modulate the TIME to reduce tumor burden in murine models. NDES achieves tumor reduction at a fourfold lower dosage than systemic treatment while avoiding treatment‐related adverse events. Further, abscopal responses are shown where intratumoral treatment yields growth inhibition in distant untreated tumors. Overall, the NDES is presented as a viable approach to penetrate the PDAC immune barrier in a minimally invasive and effective manner, for the overarching goal of transforming treatment. Nanofluidic drug‐eluting seed (NDES) enables long‐term intratumoral immunotherapeutic treatment. Sustained low‐dose agonist CD40 monoclonal antibody delivered via NDES effectively triggers anti‐tumor immune response in immunosuppressive pancreatic tumor microenvironment without treatment‐related adverse events. Overall, the NDES presents an effective low‐dose tumor‐targeted drug delivery approach for enhanced treatment efficacy and survival.