PO.IM01.10 · 免疫学
鸡尾酒免疫疗法：植物病毒免疫调节剂、HER2抗体及共递送IL-12细胞因子用于治疗HER2+癌症
Cocktail immunotherapy: Plant virus immunomodulator, HER2 antibody, and co-delivered IL-12 cytokine for the treatment of HER2+ cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
豇豆花叶病毒（CPMV）是一种感染豇豆等豆科植物的植物病毒。它已被用作小鼠癌症模型和犬类兽医临床试验中一种强效的瘤内免疫疗法。CPMV是一种多重Toll样受体（TLR）激动剂，可在局部和全身诱导强烈的抗肿瘤免疫应答。虽然作为单药疗法极为强效，但最稳健的免疫治疗方法是那些通过多个轴向靶向癌症的方法。在本研究中，我们测试了使用CPMV的瘤内免疫疗法与人表皮生长因子受体2（HER2）单克隆抗体（mAb）疗法联合靶向HER2+肿瘤。更具体地说，我们将CPMV与抗HER2 mAb或抗HER2抗体-（IL-12）融合蛋白（抗HER2抗体-（IL-12））相结合——后者是一种与细胞因子IL-12基因融合的抗HER2抗体。已知HER2扩增发生于多种癌症中，并与不良预后以及癌症复发相关。用CPMV和HER2 mAb或抗HER2抗体-（IL-12）治疗携带来自结直肠癌细胞系（MC38-HER2+和CT26-HER2+）的HER2+肿瘤的小鼠。在8周的过程中测量肿瘤体积和总生存。虽然动物对单独的HER2 mAb疗法难以应答，但使用CPMV和联合疗法实现了肿瘤生长减缓和生存增加——联合疗法的表现优于单独的CPMV疗法。这些结果表明，CPMV可与靶向抗体疗法协同以获得更强的抗肿瘤疗效。
这项工作部分由NIH资助项目R01-CA274640和R01-CA253615-02S1、NIH培训资助项目T32-CA121938、美国癌症协会院外发现科学（EDS）加速器奖EDS-24-1330440-01-EDS，以及美国癌症协会-F.M. Kirby基金会公司-Mission Boost资助项目MBGI-23-1030244-01-MBG资助。
作者声明以下相互竞争的经济利益：Steinmetz博士是PlantiosX公司的联合创始人兼CEO并持有其股权。Steinmetz博士是Mosaic Immunoengineering公司的联合创始人并持有其股权。Steinmetz博士是Pokometz Scientific LLC的联合创始人兼管理者，并以该公司名义担任Ring Therapeutics公司的付费顾问。其他作者声明无潜在利益冲突。
查看英文原文 English abstract
Cowpea Mosaic Virus (CPMV) is a plant virus which infects legumes such as cowpea plants. It has been used as a powerful intratumoral immunotherapy in murine cancer models and canine veterinary clinical trials. CPMV is a multi- Toll-Like Receptor (TLR) agonist which induces a strong anti-tumor immune response both locally and systemically. While highly potent as a monotherapy, the most robust immunotherapy approaches are those which target cancer through multiple axes. In the present work, we tested the combination of intratumoral immunotherapy using CPMV with human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb) therapy targeting HER2+ tumors. More specifically, we combined CPMV with an anti-HER2 mAb or anti-HER2 antibody-(IL-12) fusion protein (anti-HER2 antibody-(IL-12))-an anti-HER2 antibody genetically fused to the cytokine IL-12. Amplification of HER2 is known to occur in several cancers and is associated with poor prognosis as well as cancer recurrence. Mice with HER2+ tumors from colorectal cancer cell lines (MC38-HER2+ and CT26-HER2+) were treated with CPMV and HER2 mAb or anti-HER2 antibody-(IL-12). Tumor volume and overall survival were measured over the course of 8 weeks. While animals were refractory to HER2 mAb therapy alone, reduced tumor growth and increased survival was achieved using CPMV and the combination therapies- with the combination therapies outperforming CPMV therapy alone. These results indicate that CPMV can synergize with targeted antibody therapies for greater anti-tumor efficacy.
This work was funded in part through NIH grants R01-CA274640 and R01-CA253615-02S1, NIH training grant T32-CA121938, the American Cancer Society Extramural Discovery Science (EDS) Accelerator Award EDS-24-1330440-01-EDS, and the American Cancer Society - F.M. Kirby Foundation Inc. - Mission Boost Grant MBGI-23-1030244-01-MBG.
The authors declare the following competing financial interests: Dr. Steinmetz is a co-founder and CEO of and has equity in PlantiosX Inc. Dr. Steinmetz is a co-founder of and has equity in Mosaic Immunoengineering, Inc. Dr. Steinmetz is a cofounder and manager of Pokometz Scientific LLC, under which she is a paid consultant to Ring Therapeutics, Inc. The other authors declare no potential conflicts of interest.
利益披露 Disclosure
A. E. Pottenger, None..
M. A. Moreno Gonzalez, None..
N. F. Steinmetz, None.