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.

项目摘要肿瘤免疫抑制是实现有效癌症的主要障碍免疫疗法。这个探索项目的目的是开发一种新型的mRNA-lipid 基于纳米颗粒（mRNA-LNP）的免疫疗法，以克服胰腺挑战癌症，最致命的恶性肿瘤之一。目前，很少有有效的治疗方法可用于胰腺癌。大多数胰腺癌也对免疫检查点有抵抗力封锁。这是针对这种致命癌症的新型治疗策略。最多胰腺癌显示高度免疫抑制肿瘤微环境（TME）。肿瘤浸润效应子CD8+ T细胞对于改善患者生存至关重要，但它们是大多数胰腺癌中不存在或稀疏，表明有内在的机制这阻碍了T细胞浸润和激活。我们最近发现干扰素基因（STING）在胰腺和其他癌症中被沉默。因为刺激功能对于刺激抗肿瘤T细胞反应至关重要，我们的发现表明刺痛沉默有助于免疫学“冷” TME。我们发现重新激活刺痛更新细胞因子/趋化因子对于促进肿瘤内T细胞浸润至关重要。更多的重要的是，刺的重新激活特异性杀死了刺痛的癌细胞。因为肿瘤垂死的癌细胞在体内释放的抗原可能被抗原呈递细胞吞没到产生系统性抗肿瘤反应并扩大结核效应，我们假设胰腺癌中刺激的靶向重新激活可能会激发免疫阻尼 TME并改善肿瘤免疫原性。在这个项目中，我们将开发mRNA-LNP 特别将永久活跃的刺激突变体传递到胰腺癌中，以增强T细胞抗肿瘤细胞毒性。这种方法旨在克服传统刺痛的局限性激动剂，缺乏肿瘤特异性，在刺痛的癌症中不起作用。定义它们在刺激抗肿瘤免疫力方面的效率，将在体外测试STING mRNA-LNP，并且在原位合成鼠胰腺癌模型中，该模型忠实地概括了胰腺癌的免疫生物学“冷” TME。我们还将结合刺激mRNA-LNP 使用PD-1桶，将胰腺癌耐药性绕开到免疫切口治疗和刺激性抗肿瘤活性。这些临床前研究具有开发一种新型免疫疗法来克服免疫抗性和改善治疗对当前疗法难治性的一系列潜水员。