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Off-the-Shelf Prostate Stem Cell Antigen–Directed Chimeric Antigen Receptor Natural Killer Cell Therapy to Treat Pancreatic Cancer
Gastroenterology ( IF 29.4 ) Pub Date : 2022-01-06 , DOI: 10.1053/j.gastro.2021.12.281
Kun-Yu Teng 1 , Anthony G Mansour 1 , Zheng Zhu 1 , Zhiyao Li 1 , Lei Tian 1 , Shoubao Ma 1 , Bo Xu 1 , Ting Lu 1 , Hanyu Chen 1 , David Hou 1 , Jianying Zhang 2 , Saul J Priceman 3 , Michael A Caligiuri 4 , Jianhua Yu 5
Affiliation  

Background & Aims

Pancreatic cancer (PC) is the third leading cause of cancer-related death with a 5-year survival rate of approximately 10%. It typically presents as a late-stage incurable cancer and chemotherapy provides modest benefit. Here, we demonstrate the feasibility, safety, and potency of a novel human natural killer (NK) cell-based immunotherapy to treat PC.

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.



中文翻译:

现成的前列腺干细胞抗原定向嵌合抗原受体自然杀伤细胞疗法治疗胰腺癌

背景与目标

胰腺癌 (PC) 是癌症相关死亡的第三大原因,其 5 年生存率约为 10%。它通常表现为晚期无法治愈的癌症,化疗提供适度的益处。在这里,我们证明了一种新型的基于人类自然杀伤 (NK) 细胞的免疫疗法治疗 PC 的可行性、安全性和效力。

方法

在信使 RNA 和蛋白质水平上评估初级 PC 中前列腺干细胞抗原 (PSCA) 的表达。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得到优化,使我们能够开发冷冻、现成的同种异体 PSCA 嵌合抗原受体 (CAR) NK 细胞。在体外和体内评估了同时表达可溶性白细胞介素 15(PSCA CAR_s15 NK 细胞)的 PSCA CAR NK 细胞的安全性和有效性。

结果

与邻近或其他正常组织相比,PSCA 在原发性人类 PC 中升高。在 1 个冻融循环前后,PSCA CAR_s15 NK 细胞在体外对 PSCA(+) PC 显示出显着的肿瘤抑制作用。冷冻的 PSCA CAR_s15 NK 细胞在最后一次输注后的体内存活时间超过 90 天,并显着延长了植入人类 PC 的小鼠的存活时间。

结论

PSCA CAR_s15 NK 细胞在人类转移性 PC 模型中显示出治疗效果,没有系统毒性迹象,为支持临床开发提供了强有力的理论依据。

更新日期:2022-01-06
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