RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
现货型前列腺干细胞抗原导向嵌合抗原受体 NK 细胞疗法治疗胰腺癌
英文原题：Off-the-Shelf Prostate Stem Cell Antigen-Directed Chimeric Antigen Receptor Natural Killer Cell Therapy to Treat Pancreatic Cancer.
查看英文原题
Off-the-Shelf Prostate Stem Cell Antigen-Directed Chimeric Antigen Receptor Natural Killer Cell Therapy to Treat Pancreatic Cancer.
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研究概要
PSCA CAR_s15 NK 细胞在人转移性 PC 模型中显示出治疗效果，且无系统性毒性迹象，为支持临床开发提供了有力依据。
研究思路结论见上方概要
目的
胰腺癌（PC）是癌症相关死亡的第三大原因，5年生存率约为10%。它通常表现为晚期不可治愈的癌症，化疗提供的益处有限。在此，我们展示了一种新型人自然杀伤（NK）细胞免疫疗法治疗PC的可行性、安全性和效力。
方法
前列腺干细胞抗原（PSCA）在原发PC中的表达在信使RNA和蛋白质水平进行了评估。对从脐带血中获得的原代人NK细胞的逆转录病毒转导、扩增、激活和冷冻保存过程进行了优化，使我们能够开发出冷冻、即用型、同种异体PSCA嵌合抗原受体（CAR）NK细胞。同时表达可溶性（s）白细胞介素15的PSCA CAR NK细胞（PSCA CAR_s15 NK细胞）的安全性和有效性在体外和体内进行了评估。
结果
PSCA在原发性人PC中较邻近组织或其他正常组织升高。PSCA CAR_s15 NK细胞在体外对PSCA(+) PC表现出显著的抑瘤作用，且在1个冻融周期前后均如此。冻存的PSCA CAR_s15 NK细胞在末次输注后体内活力维持超过90天，并显著延长了移植人PC小鼠的生存期。
展开英文摘要原文
METHODS
The expression of prostate stem cell antigen (PSCA) was evaluated in primary PC at messenger RNA and protein levels. The processes of retroviral transduction, expansion, activation, and cryopreservation of primary human NK cells obtained from umbilical cord blood were optimized, allowing us to develop frozen, off-the-shelf, allogeneic PSCA chimeric antigen receptor (CAR) NK cells. The safety and efficacy of PSCA CAR NK cells also expressing soluble (s) interleukin 15 (PSCA CAR_s15 NK cells) were evaluated in vitro and in vivo.
RESULTS
PSCA was elevated in primary human PC compared with the adjacent or other normal tissues. PSCA CAR_s15 NK cells displayed significant tumor-suppressive effects against PSCA(+) PC in vitro before and after 1 cycle of freeze-thaw. The viability of frozen PSCA CAR_s15 NK cells persisted more than 90 days in vivo after their last infusion and significantly prolonged the survival of mice engrafted with human PC.
CONCLUSIONS
PSCA CAR_s15 NK cells showed therapeutic efficacy in human metastatic PC models without signs of systematic toxicity, providing a strong rationale to support clinical development.
论文信息
- 作者
- Teng KY、Mansour AG、Zhu Z、Li Z、Tian L、Ma S、Xu B、Lu T
- 第一作者单位
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California.United States
- 通讯作者单位
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California; Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Centre, Los Angeles, California; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California; City of Hope Comprehensive Cancer Center, Los Angeles, California. Electronic address: jiayu@coh.org.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Gastroenterology2022 Apr
- 原文标识
- PubMed 34999097 · DOI 10.1053/j.gastro.2021.12.281