Background: Surgery, chemotherapy, and radiation often have limited utility for advanced metastatic disease in the liver, and despite its promising activity in select cancers, PD-1 blockade therapy similarly has minimal benefit in this setting. Curaxin, CBL0137, is an experimental anti-cancer drug that disrupts the binding of DNA to histones, destabilizes chromatin, and induces Z-DNA formation which may stimulate anti-tumor immune responses. Methods: Murine cell lines of colon (CT26) and breast (4T1) cancer were interrogated for survival and CBL0137-associated DNA changes in vitro. Immunocompetent models of liver metastases followed by CBL0137 hepatic arterial infusion (HAI) were used to examine in vivo tumor cell DNA alterations, treatment responses, and the immune contexture associated with CBL0137, both alone and in combination with anti-PD-1 therapy. Results: CBL0137 induced immediate changes to favor tumor cell death in vitro and in vivo with an efficient tumor uptake via the HAI route. Toxicity to CBL0137 was minimal and anti-tumor treatment effects were more efficient with HAI compared to intravenous delivery. Immune effects were pronounced with CBL0137 HAI with concurrent depletion of a specific population of myeloid-derived suppressor cells and maintenance of effector T cell populations. Conclusions: Combination of CBL0137 HAI with PD-1 blockade improved survival in 4T1 tumors but not in CT26 tumors, and therapeutic efficacy relies on the finding of simultaneous and targeted depletion of myeloid-derived suppressor cells and skewing of T cell populations to produce synergy with PD-1 blockade therapy.
背景：对于肝脏晚期转移性疾病，手术、化疗和放疗的疗效往往有限，尽管PD-1阻断疗法在某些癌症中显示出良好前景，但在此类疾病中同样收效甚微。Curaxin类药物CBL0137是一种实验性抗癌药物，能破坏DNA与组蛋白的结合、使染色质失稳并诱导Z-DNA形成，从而可能激发抗肿瘤免疫反应。 方法：本研究在体外检测了结肠癌（CT26）和乳腺癌（4T1）小鼠细胞系的存活率及CBL0137诱导的DNA变化。通过建立免疫健全的肝转移模型，采用CBL0137肝动脉灌注（HAI）给药方式，单独或联合抗PD-1疗法，观察体内肿瘤细胞DNA变化、治疗反应及CBL0137相关的免疫微环境特征。 结果：CBL0137通过HAI途径能高效被肿瘤摄取，在体外和体内均能立即引发促进肿瘤细胞死亡的变化。与静脉给药相比，CBL0137的HAI给药方式毒性更小且抗肿瘤效果更显著。CBL0137 HAI能产生显著的免疫效应，表现为同时耗竭特定髓源性抑制细胞亚群并维持效应T细胞群。 结论：CBL0137 HAI联合PD-1阻断疗法能提高4T1肿瘤模型的生存率，但对CT26模型无效。该疗法的有效性取决于能否同时靶向耗竭髓源性抑制细胞并调控T细胞群，从而与PD-1阻断疗法产生协同作用。
肿瘤(癌症)患者之家