A novel gene therapy approach targeting STING-silenced cold tumors

一种针对 STING 沉默冷肿瘤的新型基因治疗方法

基本信息

批准号：
10577939
负责人：
Jianxin You
金额：
$ 22.79万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-09 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10577939
关键词：
Agonist Antibody Therapy Antigen-Presenting Cells Antitumor Response Biological Assay Biological Response Modifiers CD8-Positive T-Lymphocytes COVID-19 vaccine Chemotactic Factors Clinical Collaborations Development Diagnosis Effectiveness Engineering Face Gene Silencing Goals Grant Human Hyperactivity Immune Immune checkpoint inhibitor Immune system Immunologics Immunosuppression Immunotherapy In Vitro Infiltration Legal patent Letters Link Malignant Neoplasms Malignant neoplasm of pancreas Messenger RNA Methods Mus PD-1 blockade PD-1/PD-L1 Pancreas Pancreatic Ductal Adenocarcinoma Patients Peptides Production Publishing RNA Repression Resistance Stimulator of Interferon Genes T cell infiltration T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Tissues Toxic effect Translating Treatment outcome Tumor Antigens Tumor Immunity Work advanced pancreatic cancer anti-PD1 antibodies anti-cancer autoinflammatory diseases cancer cell cancer immunotherapy cell killing checkpoint therapy chemokine cytokine cytotoxicity effective therapy engineered T cells gene function gene repression gene therapy immune checkpoint blockade immune resistance immunogenicity implantation improved in vitro testing in vivo lipid nanoparticle mRNA Expression migration multidisciplinary mutant neoplastic cell new therapeutic target novel novel therapeutic intervention pancreatic cancer model pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model preclinical study prevent refractory cancer success synergism therapeutic nanoparticles tumor tumor DNA tumor microenvironment tumor specificity tumor-immune system interactions ultrasound

项目摘要

Project Summary Tumor immune suppression represents a major obstacle in achieving effective cancer immunotherapy. The goal of this exploratory project is to develop a novel mRNA-lipid nanoparticle (mRNA-LNP)-based immunotherapy to overcome this challenge in pancreatic cancer, one of the deadliest malignancies. Currently, few effective treatments are available for pancreatic cancer. The majority of pancreatic cancers are also resistant to immune checkpoint blockade. Thus, novel therapeutic strategies are needed to target this lethal cancer. Most pancreatic cancers display a highly immunosuppressive tumor microenvironment (TME). Tumor-infiltrating effector CD8+ T cells are critical for improved patient survival, and yet they are either absent or sparse in the majority of pancreatic cancers, indicating an intrinsic mechanism that impedes T cell infiltration and activation. We recently discovered that Stimulator of Interferon Genes (STING) is silenced in pancreatic and other cancers. Because STING function is critical for stimulating antitumor T cell responses, our finding suggests that STING silencing contributes to the immunologically “cold” TME. We found that reactivating STING upregulates cytokines/chemokines that are crucial for promoting intratumoral T cell infiltration. More importantly, reactivation of STING specifically kills STING-silenced cancer cells. Because tumor antigens released by dying cancer cells in vivo could be engulfed by antigen-presenting cells to generate systemic antitumor response and amplify tumoricidal effect, we hypothesize that targeted reactivation of STING in pancreatic cancer could invigorate the immune-dampened TME and improve tumor immunogenicity. In this project, we will develop mRNA-LNP to specifically deliver permanently active STING mutants into pancreatic cancer to bolster T cell antitumor cytotoxicity. This approach aims to overcome the limitations of traditional STING agonists, which lack tumor specificity and do not work in STING-silenced cancers. To define their efficacy in stimulating antitumor immunity, the STING mRNA-LNP will be tested in vitro and in an orthotopic syngeneic murine pancreatic cancer model, which faithfully recapitulates the immunobiologically “cold” TME of pancreatic cancer. We will also combine STING mRNA-LNP with PD-1 blockade to circumvent pancreatic cancer resistance to the immune checkpoint therapy and spur synergistic antitumoral activity. These preclinical studies have the potential for developing a novel immunotherapy to overcome immune resistance and improve treatments for a diverse array of STING-silenced cancers that are refractory to current therapies.

项目概要肿瘤免疫抑制是实现有效癌症治疗的主要障碍该探索性项目的目标是开发一种新型 mRNA-脂质。基于纳米颗粒（mRNA-LNP）的免疫疗法可克服胰腺中的这一挑战癌症是最致命的恶性肿瘤之一，目前几乎没有有效的治疗方法。大多数胰腺癌也对免疫检查点有抵抗力。因此，需要新的治疗策略来针对这种致命的癌症。胰腺癌表现出高度免疫抑制的肿瘤微环境（TME）。肿瘤浸润效应 CD8+ T 细胞对于改善患者生存至关重要，但它们大多数胰腺癌中不存在或稀疏，表明存在内在机制我们最近发现了阻碍 T 细胞浸润和激活的刺激物。干扰素基因 (STING) 在胰腺癌和其他癌症中被沉默，因为 STING 发挥作用。对于刺激抗肿瘤 T 细胞反应至关重要，我们的发现表明 STING 沉默我们发现重新激活 STING 会上调免疫学上的“冷”TME。对于促进肿瘤内 T 细胞浸润至关重要的细胞因子/趋化因子。重要的是，STING 的重新激活可以特异性杀死 STING 沉默的癌细胞。体内垂死的癌细胞释放的抗原可以被抗原呈递细胞吞噬，产生全身抗肿瘤反应并放大肿瘤杀伤作用，我们勇敢地说胰腺癌中 STING 的靶向重新激活可以激活免疫减弱的细胞 TME 并提高肿瘤免疫原性在这个项目中，我们将开发 mRNA-LNP。特异性地将永久活性的 STING 突变体递送到胰腺癌中以增强 T 细胞该方法旨在克服传统 STING 的局限性。激动剂，缺乏肿瘤特异性，对 STING 沉默的癌症不起作用。 STING mRNA-LNP 在刺激抗肿瘤免疫方面的功效将在体外进行测试在原位同基因小鼠胰腺癌模型中，该模型忠实地再现了我们还将结合 STING mRNA-LNP 进行胰腺癌的免疫生物学“冷”TME。通过 PD-1 阻断来规避胰腺癌对免疫检查点的抵抗这些临床前研究具有潜在的治疗和刺激协同抗肿瘤活性的作用。开发一种新型免疫疗法来克服免疫抵抗并改善治疗一系列通过 STING 沉默的癌症对当前的治疗方法无效。