晚期肝肿瘤的治疗仍然具有挑战性。尽管免疫检查点抑制彻底改变了许多癌症的治疗，但结直肠肝转移和胆道癌的反应仍然不理想。需要对这些癌症的其他免疫调节疗法进行研究。白细胞介素-12 (IL-12) 是一种促炎细胞因子，具有强大的抗肿瘤活性，但全身性副作用很大程度上终止了重组人 IL-12 (rhIL-12) 的治疗开发。 PDS01ADC 是一种新型人单克隆抗体 (NHS76)，与两个 IL-12 异二聚体缀合，在 I 期试验中已确定安全性。 NHS76 抗体专门针对组蛋白/DNA 复合物，该复合物仅在细胞死亡区域才可接触，并且该抗体已被证明会在肿瘤中局部积累。患有不可切除的转移性结直肠癌 (mCRC) 或不可切除的肝内胆管癌 (ICC) 的患者将接受同步治疗皮下注射 PDS01ADC，通过肝动脉输液泵 (HAIP) 输送氟尿苷。本研究测量的主要结果是根据实体瘤反应评估标准 (RECIST) 标准测量的总体反应率。本研究测量的次要结果将包括肝脏和非肝脏的无进展生存期 (PFS)、总生存期以及 PDS01ADC 与 HAIP 联合治疗的安全性。这些肝脏肿瘤对免疫治疗的临床反应不佳可能是由于多种因素造成的，包括肿瘤的免疫浸润不良以及肿瘤微环境的免疫抑制。通过利用 HAIP 局部治疗联合全身化疗诱导的肿瘤细胞死亡，PDS01ADC 有望调节肿瘤免疫微环境，以改善接受 HAIP 治疗的患者的预后。ClinicalTrials.gov（ID NCT05286814 版本 2023-10-18）； https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814

Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors.Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP.Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy.ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.2024 Journal of Gastrointestinal Oncology. All rights reserved.