Targeting STAT3 to enhance anti-tumor immunity

靶向STAT3增强抗肿瘤免疫力

基本信息

批准号：
10405428
负责人：
Jennifer Rubin Grandis
金额：
$ 63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-13 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405428
关键词：
Address Animal Model Animals Antineoplastic Agents Apoptosis Binding Cell Maturation Cell Proliferation Cell physiology Cells Clinical Clinical Trials Dendritic Cells Evaluation Exhibits Felis catus Foundations Future Genes Growth Head Cancer Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Hematopoietic Human Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunodeficient Mouse Immunologics Immunosuppression Injections Malignant Neoplasms Maximum Tolerated Dose Mediating Mediator of activation protein Molecular Target Morbidity - disease rate Mus Myeloid-derived suppressor cells Natural Killer Cells Natural Products Nature Nivolumab Oligonucleotides Oncogenic Patient-Focused Outcomes Periodicity Phase Phase 0 Clinical Trial Phase 0 Trial Phase I Clinical Trials Phosphorylation Population Production Prognosis Protein Tyrosine Kinase Proteins Quality of life Regulation Regulatory T-Lymphocyte Resistance Response Elements Role Safety Specificity Stat3 protein Survival Rate T-Lymphocyte Subsets Testing Time Toxic effect Tumor Immunity Tumor-infiltrating immune cells antitumor effect cell growth checkpoint inhibition cytokine design effector T cell immune activation improved improved outcome inhibitor innovation mouse model mutant neoplastic cell neutrophil novel nuclease patient subsets pembrolizumab programmed cell death protein 1 promoter receptor small molecule survival outcome transcription factor tumor tumor growth tumor microenvironment tumor xenograft

项目摘要

ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is a common and lethal cancer, where 5-year survival rates have lingered at roughly 40-60% for several decades. Our long-term objective is to develop effective, well-tolerated agents and strategies to improve the outcomes of patients with HNSCC. The recent approval of the PD-1 checkpoint inhibitors nivolumab and pembrolizumab for HNSCC suggests that targeting central mediators of immunosuppression in the tumor microenvironment will lead to significant improvements in treatment. Inhibition of the oncogenic transcription factor STAT3 represents a promising new strategy for relieving immunosuppression. STAT3 is hyperactivated in HNSCC, where it contributes to tumor growth, production of immunosuppressive cytokines, and poor prognosis. STAT3 is also hyperactivated in tumor infiltrating immune cells. Conditional deletion of stat3 in murine hematopoietic cells has revealed potent immunosuppressive roles for STAT3 in multiple immune cell populations. Thus, selective targeting of STAT3 may yield a three-fold anti-tumor benefit: a) direct inhibition of tumor cell growth, b) inhibition of cell- autonomous immunosuppression in immune cells, and c) relief of immunosuppressive cross-talk between tumor and immune cells. However, currently available STAT3 inhibitors either lack potency and specificity, or cannot be delivered systemically. To overcome this obstacle we designed a 15-bp duplex oligonucleotide, the STAT3 decoy, which resembles a STAT3 response element, binds selectively to activated STAT3, induces HNSCC apoptosis, and suppresses the growth of xenograft tumors. A Phase 0 trial involving intratumoral injection of this STAT3 decoy demonstrated downmodulation of STAT3 target genes in HNSCC tumors. A cyclic version of STAT3 decoy exhibits improved stability and nuclease resistance, and inhibits the growth of xenograft tumors following systemic delivery to immunodeficient mice. The impact of the cyclic STAT3 decoy on the immune system has never been studied, limiting the design of further clinical trials with this promising anti-cancer agent. We will utilize immunocompetent murine models of HNSCC to rigorously evaluate the effects on the immune system of cyclic STAT3 decoy, alone and in combination with PD-1 inhibition. In addition, we will evaluate safety, immune effects and potential efficacy, of the cyclic STAT3 decoy in a unique and valuable animal model of naturally occurring HNSCC in pet cats. Our studies will test the hypothesis that targeted inhibition of STAT3 via systemic administration of cyclic STAT3 decoy will enhance anti-tumor immunity in immunocompetent mouse models of HNSCC and augment the effects of PD-1 checkpoint inhibition, while exhibiting minimal toxicity in pet cats with naturally occurring HNSCC. Results from our studies will determine the potential for relieving immunosuppression in HNSCC using cyclic STAT3 decoy, while laying the foundation for clinical advancement of this highly innovative and selective STAT3 inhibitor.

抽象的头颈部鳞状细胞癌（HNSCC）是一种常见的致命癌症，其中5年生存数十年来，利率持续了大约40-60％。我们的长期目标是发展有效，耐受性良好的药物和改善HNSCC患者预后的策略。最近的认可 PD-1检查点抑制剂Nivolumab和pembrolizumab用于HNSCC，这表明针对中央肿瘤微环境中免疫抑制介质将导致显着改善治疗。抑制致癌转录因子STAT3代表了一种有希望的新策略缓解免疫抑制。 STAT3在HNSCC中过度活化，在此促进肿瘤生长，免疫抑制细胞因子的产生和预后不良。 STAT3在肿瘤中也过度活化浸润免疫细胞。在鼠造血细胞中STAT3的有条件缺失已显示出有效的 STAT3在多个免疫细胞群中的免疫抑制作用。因此，STAT3的选择性定位可能产生三倍的抗肿瘤益处：a）直接抑制肿瘤细胞生长，b）抑制细胞免疫细胞中的自主免疫抑制，c）缓解免疫抑制肿瘤和免疫细胞。但是，目前可用的STAT3抑制剂要么缺乏效力和特异性，要么无法系统地交付。为了克服这一障碍，我们设计了15 bp的双工寡核苷酸，类似于STAT3响应元件的STAT3诱饵与激活的STAT3有选择性结合，诱导 HNSCC凋亡，并抑制异种移植肿瘤的生长。涉及肿瘤内的0期试验注射该STAT3诱饵表明HNSCC肿瘤中STAT3靶基因的下调。一个 STAT3诱饵的环状版本具有改善的稳定性和核酸酶耐药性，并抑制了全身递送到免疫缺陷小鼠后的异种移植肿瘤。环状STAT3诱饵的影响从未研究过免疫系统，限制了这种有前途的进一步临床试验的设计抗癌代理。我们将利用HNSCC的免疫能力鼠模型严格评估单独并与PD-1抑制作用的循环STAT3诱饵的免疫系统的影响。在此外，我们将评估环环诱饵的安全性，免疫效应和潜在功效以及宠物猫中天然HNSCC的宝贵动物模型。我们的研究将检验以下假设通过系统给药的靶向抑制STAT3抑制循环STAT3诱饵将增强抗肿瘤 HNSCC的免疫能力小鼠模型的免疫力并增强PD-1检查点的影响抑制作用，同时在天然存在HNSCC的宠物猫中表现出最小的毒性。我们的结果研究将确定使用Cyclic Stat3诱饵，减轻HNSCC免疫抑制的潜力，同时为这种高度创新和选择性的STAT3抑制剂奠定了基础。