肿瘤细胞治疗研究
英文原题：Recurrent pancreatic cancer treated with N-803 and PD-L1 t-haNK followed by an EGFR-targeted nanocell drug conjugate.
在初始的单患者研究性新药（spIND）方案下，该患者接受了 N-803、PD-L1 t-haNK 细胞和白蛋白多柔比星偶联物 aldoxorubicin 治疗约 27 个月。
通过协调免疫治疗、肿瘤靶向化疗和自然杀伤（NK）细胞治疗的多模式序贯疗法，可能诱导免疫原性细胞死亡、促使肿瘤应答，并延长复发癌症患者的生存期。白细胞介素 15（IL-15）超级激动剂 N-803 可增强 NK 细胞、CD4+ T 细胞、细胞毒性 CD8+ T 细胞及记忆 T 细胞活性；与现成型、高亲和力靶向 PD-L1 的 NK（PD-L1 t-haNK）细胞联合，是旨在克服免疫抑制性肿瘤微环境（TME）的新型免疫疗法。靶向表皮生长因子受体的抗体-纳米细胞偶联物 E-EDV-D682 可通过递送蒽环类代谢物 PNU159682（nemorubicin）提供肿瘤靶向化疗，目前正在与递送佐剂 α-半乳糖神经酰胺（GC）的免疫调节 EDV 联合研究。本文报告一例经 3 线治疗后复发转移性胰腺癌（mPC）患者接受该联合方案同情用药的情况。在初始单患者新药（spIND）方案下，患者接受 N-803、PD-L1 t-haNK 细胞及白蛋白-doxorubicin 偶联物 aldoxorubicin 治疗约 27 个月。患者病情在该方案下稳定，并在治疗约 14 个月时短暂达到完全缓解。病情进展后，设计了第二项 spIND 方案，患者接受 E-EDV-D682 联合 EDV-GC 治疗超过 24 个月，病情稳定，并在本报告撰写时仍存活。尽管复发 mPC 预后极差，患者仍获得较长生存期，提示这一序贯联合方案可能通过增强免疫活性克服免疫和化疗耐药，从而促进肿瘤应答并延长生存。
Multimodal temporal therapy orchestrated to leverage immunotherapy, tumor-targeted chemotherapy, and natural killer (NK) cell therapy may provide an opportunity to induce immunogenic cell death for tumor response and increased survival in patients with recurrent cancer. The interleukin-15 (IL-15) superagonist N-803, an enhancer of NK cells, CD4 + T cells, cytotoxic CD8 + T cells, and memory T-cell activity, combined with off-the-shelf PD-L1-targeted high-affinity NK (PD-L1 t-haNK) cells represent novel immunotherapies designed to overcome an immunosuppressive tumor microenvironment (TME). The epidermal growth factor receptor-targeted antibody-nanocell conjugate E-EDV-D682 provides tumor-targeted chemotherapy in the form of its anthracycline metabolite PNU159682 (nemorubicin) cargo and is currently being studied in combination with immunomodulatory EDVs delivering the adjuvant -galactosyl ceramide (GC). Here, we report the compassionate use treatment of this combination in a patient with recurrent, metastatic pancreatic cancer (mPC) after 3 lines of therapy. Under the initial single-patient Investigational New Drug (spIND) protocol, the patient received N-803, PD-L1 t-haNK cells, and the albumin doxorubicin conjugate aldoxorubicin for ~27 months. The patient's disease became stable on this regimen, and a transient complete response was observed by ~14 months of therapy. Due to progression, a second spIND protocol was designed whereby the patient received E-EDV-D682 plus EDV-GC for more than 24 months, which resulted in stable disease and the patient's continued survival at the time this report was written. The patient's extended survival despite the dire prognosis associated with recurrent mPC points to the merits of this temporal combination regimen in overcoming immuno-chemo resistance with enhanced immune activity required for tumor response and extended survival.
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