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溶瘤腺病毒免疫疗法调节免疫系统，使 CAR T 细胞能够治愈胰腺肿瘤。

Oncolytic adeno-immunotherapy modulates the immune system enabling CAR T-cells to cure pancreatic tumors.

机构信息

Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA.

Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA.

出版信息

Commun Biol. 2021 Mar 19;4(1):368. doi: 10.1038/s42003-021-01914-8.

DOI:10.1038/s42003-021-01914-8
PMID:33742099
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7979740/
Abstract

High expression levels of human epidermal growth factor receptor 2 (HER2) have been associated with poor prognosis in patients with pancreatic adenocarcinoma (PDAC). However, HER2-targeting immunotherapies have been unsuccessful to date. Here we increase the breadth, potency, and duration of anti-PDAC HER2-specific CAR T-cell (HER2.CART) activity with an oncolytic adeno-immunotherapy that produces cytokine, immune checkpoint blockade, and a safety switch (CAdTrio). Combination treatment with CAdTrio and HER2.CARTs cured tumors in two PDAC xenograft models and produced durable tumor responses in humanized mice. Modifications to the tumor immune microenvironment contributed to the antitumor activity of our combination immunotherapy, as intratumoral CAdTrio treatment induced chemotaxis to enable HER2.CART migration to the tumor site. Using an advanced PDAC model in humanized mice, we found that local CAdTrio treatment of primary tumor stimulated systemic host immune responses that repolarized distant tumor microenvironments, improving HER2.CART anti-tumor activity. Overall, our data demonstrate that CAdTrio and HER2.CARTs provide complementary activities to eradicate metastatic PDAC and may represent a promising co-operative therapy for PDAC patients.

摘要

高表达水平的人类表皮生长因子受体 2（HER2）与胰腺导管腺癌（PDAC）患者的预后不良有关。然而，迄今为止，HER2 靶向免疫疗法并不成功。在这里，我们使用一种能够产生细胞因子、免疫检查点阻断和安全开关的溶瘤腺病毒免疫疗法（CAdTrio），提高了抗 PDAC HER2 特异性嵌合抗原受体 T 细胞（HER2.CART）的广度、效力和持续时间。CAdTrio 与 HER2.CART 的联合治疗可治愈两种 PDAC 异种移植模型中的肿瘤，并在人源化小鼠中产生持久的肿瘤反应。肿瘤免疫微环境的改变有助于我们联合免疫疗法的抗肿瘤活性，因为肿瘤内 CAdTrio 治疗诱导趋化作用，使 HER2.CART 迁移到肿瘤部位。在人源化小鼠的先进 PDAC 模型中，我们发现局部 CAdTrio 治疗原发性肿瘤刺激了全身宿主免疫反应，使远处肿瘤微环境重新极化，从而提高了 HER2.CART 的抗肿瘤活性。总的来说，我们的数据表明，CAdTrio 和 HER2.CART 提供了互补的活性，可以根除转移性 PDAC，可能代表 PDAC 患者的一种有前途的联合治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/a53435b2f3e2/42003_2021_1914_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/1c49d1316718/42003_2021_1914_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/45ffe08b5156/42003_2021_1914_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/d633241fd121/42003_2021_1914_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/c633dc6c3ad3/42003_2021_1914_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/71f261528d10/42003_2021_1914_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/a53435b2f3e2/42003_2021_1914_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/1c49d1316718/42003_2021_1914_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/45ffe08b5156/42003_2021_1914_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/d633241fd121/42003_2021_1914_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/c633dc6c3ad3/42003_2021_1914_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/71f261528d10/42003_2021_1914_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8854/7979740/a53435b2f3e2/42003_2021_1914_Fig6_HTML.jpg

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