权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要