Engineered VNP20009 expressing IL-15&15Rα augments anti-tumor immunity for bladder cancer treatment

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials Pub Date : 2024-11-06 DOI:10.1016/j.biomaterials.2024.122951

Bo Liu , Kaiwei Wang , Qiaofeng Li , Zhisheng Xiao , Zihao Chen , Yuting Zhang , Yuzhe Wu , Yuchun Xu , Yumin Wu , Zhuang Liu

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引用次数: 0

Abstract

Surgical resection combined with intravesical instillation of chemotherapeutics or Bacillus Calmette-Guerin (BCG) to remove residual cancer cells is the gold standard for the clinical treatment of patients with bladder cancer. In a recent clinical trial, a new super-agonist complex of IL-15 - N803, has shown promising results when used in combination with BCG to treat patients with bladder cancer who do not respond to BCG. Herein, we used temperature-controlled pBV220 plasmid encoding Interleukin-15 and its receptor alpha subunit (IL-15&15Rα) to transform VNP20009, an attenuated salmonella typhimurium strain, obtaining engineered bacteria named 15&15Rα@VNP. After induction at 42 °C, 15&15Rα@VNP can secrete functional IL-15&15Rα stably. It was found that intravesical instillation of thermally activated 15&15Rα@VNP could inhibit the growth of bladder tumors if used alone. Moreover, the sequential intravesical instillation of epirubicin (EPI), a first-line bladder cancer drug, followed by thermally activated 15&15Rα@VNP, could achieve further improved therapeutic responses, without causing significant side effects. Therefore, this study shows that 15&15Rα@VNP can be effectively used in the treatment of bladder cancer and can be used as a complementary therapy to chemotherapy agents, promising for potential clinical translation in bladder cancer treatment.

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表达 IL-15&15Rα 的工程 VNP20009 增强了治疗膀胱癌的抗肿瘤免疫力。

手术切除结合膀胱内灌注化疗药物或卡介苗（BCG）以清除残余癌细胞是临床治疗膀胱癌患者的金标准。在最近的一项临床试验中，一种新型 IL-15 超级拮抗剂复合物 N803 与卡介苗联合使用，治疗对卡介苗无效的膀胱癌患者，取得了良好的效果。在此，我们使用编码白细胞介素-15及其受体α亚基（IL-15&15Rα）的温控pBV220质粒转化减毒鼠伤寒沙门氏菌菌株VNP20009，获得了名为15&15Rα@VNP的工程菌。经 42 ℃ 诱导后，15&15Rα@VNP 可稳定分泌功能性 IL-15&15Rα。研究发现，单独使用热激活的 15&15Rα@VNP 静脉内灌注可抑制膀胱肿瘤的生长。此外，在膀胱癌一线药物表柔比星（EPI）和热活化 15&15Rα@VNP 的静脉内连续灌注后，可进一步提高治疗效果，且不会产生明显的副作用。因此，这项研究表明，15&15Rα@VNP 可有效用于膀胱癌的治疗，并可作为化疗药物的辅助疗法，有望在膀胱癌治疗领域实现临床转化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomaterials 工程技术-材料科学：生物材料

CiteScore

26.00

自引率

2.90%

发文量

565

审稿时长

46 days

期刊介绍： Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.