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Development of T cell-mediated targeted gene delivery of immunotoxin in HNSCC

T 细胞介导的 HNSCC 免疫毒素靶向基因递送的开发

基本信息

批准号：
10438891
负责人：
GUIQIN XIE
金额：
$ 15.45万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438891
关键词：
Aftercare Antibodies Antigen Targeting Blood Body Weight C57BL/6 Mouse Cell surface Cells Clinical Development Diagnosis Diphtheria Toxin EGFR Protein Overexpression Engineering Epidermal Growth Factor Receptor Evaluation FDA approved Gene Delivery Glioma Goals Head and Neck Squamous Cell Carcinoma Hematologic Neoplasms Hematopoietic Neoplasms Human Immune response Immunocompetent Immunodeficient Mouse Immunotherapy Immunotoxins Lentivirus Lentivirus Vector Malignant Epithelial Cell Malignant Neoplasms Measures Mediating Mesothelioma Minority Mus Patients Pichia Production Protein Biosynthesis Proteins Recombinants Recurrence Research Project Grants Resistance Solid Solid Neoplasm Stream System T-Cell Development T-Lymphocyte Tail Therapeutic Therapeutic Agents Toxic effect Tumor Antigens Tumor Tissue Validation Veins alpha Toxin cancer cell chemotherapy clinical application effective therapy efficacy evaluation engineered T cells experience expression vector immunogenic immunogenicity improved in vitro activity inducible gene expression mouse model mutant neoplastic cell neutralizing antibody notch protein novel novel strategies overexpression preclinical study prevent promoter receptor response targeted treatment transcription factor tumor vector

项目摘要

Development of T cell-mediated targeted gene delivery of immunotoxin in HNSCC Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with more than 500,000 new cases diagnosed annually. Chemotherapy, targeted treatment, and immunotherapy have been approved by the FDA for HNSCC treatment. While a minority of patients experience dramatic long-lasting and favorable clinical responses, the majority of patients fail to achieve durable clinical response. Thus, alternative options with improved beneficial response are urgently needed. In HNSCC, over 90% of tumors overexpress cell surface EGFR. Recombinant immunotoxin (RIT) is a fused protein often consisting of an antibody that targets a tumor antigen and a toxin (e.g., diphtheria toxin [DT]) that kills tumor cells. RIT has been shown to be extremely effective for the treatment of some hematopoietic malignancies. However, RIT is a highly immunogenic and very toxic protein, preventing its use as an effective treatment for solid tumors, including HNSCC. In our previous studies, we produced a humanized RIT DT390-HuBiscFv806 (hDT806) targeting EGFR and demonstrated the efficacy of hDT806 in treating HNSCC and glioma. In this proposal, we will develop a novel approach to overcome the critical limitations of the current RIT application for treating HNSCC with two specific aims. Aim 1: to eliminate systemic immunogenicity and reduce RIT-induced toxicity, we will engineer synthetic Notch T cells to deliver hDT806, specifically targeting HNSCC tumor cells that overexpress EGFR. Aim 2: we will determine the efficacy of hDT806 for killing tumor cells and toxicity in immunodeficient and immunocompetent mice. The validation of scientific principles to effectively and safely deliver RIT will provide a solid rationale for a subsequent research project grant (R01) application to use RIT as a therapeutic agent in recurrent or metastatic HNSCC for which treatment options remain extremely limited.

HNSCC中T细胞介导免疫毒素靶向基因传递的研究进展

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recombinant immunotoxin induces tumor intrinsic STING signaling against head and neck squamous cell carcinoma.

DOI：
10.1038/s41598-023-45797-7
发表时间：
2023-10-28
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Xie, Guiqin;Shan, Liang;Yang, Cuicui;Liu, Yuanyi;Pang, Xiaowu;Teng, Shaolei;Wu, Tzyy-Choou;Gu, Xinbin
通讯作者：
Gu, Xinbin

Bidirectional CART.BiTE cells bring new hope.