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Focused ultrasound control of intratumoral NKG2DL BTE production by CART cells to potentiate epitope spread

聚焦超声控制 CART 细胞瘤内 NKG2DL BTE 的产生，以增强表位扩散

基本信息

批准号：
10656254
负责人：
Ali Zamat
金额：
$ 4.77万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
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：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656254
关键词：
Adoptive Cell Transfers Adverse effects Adverse event Antibodies Antigen Targeting Antigens Antitumor Response Autoimmunity Body Temperature Breast Cancer Model CAR T cell therapy CD3 Antigens Cell physiology Cells Clinical Continuous Infusion Deposition Diffusion Diphtheria Toxin Drug Delivery Systems Drug Kinetics ERBB2 gene Effectiveness Epitope spreading Epitopes Exposure to FDA approved FLT3 ligand Focused Ultrasound Genetic Transcription Half-Life Heating Hematologic Neoplasms Human Image Immune Immune response Immune system Immunity Immunocompetent Immunological Models Immunomodulators Immunophenotyping In Vitro Infiltration Investigation Life Ligands Local Hyperthermia Malignant Neoplasms Measurement Measures Mediating Mus Natural Killer Cells Patients Production Prognosis Proliferating Recurrent disease Reporting Rest Self Tolerance Site Solid Neoplasm Specificity Spleen Stress Surveys Switch Genes Systemic Therapy T cell therapy T-Cell Activation T-Lymphocyte Techniques Tissues Toxic effect Transgenes Transgenic Mice Trastuzumab Tumor Antigens Tumor Burden Tumor Escape Tumor Immunity Ultrasonic wave bi-specific T cell engager cancer type cell killing chimeric antigen receptor chimeric antigen receptor T cells clinical care cytokine cytokine release syndrome cytotoxicity delivery vehicle design engineered T cells immune cell infiltrate immunoregulation improved in vivo long term memory lymph nodes malignant breast neoplasm member migration mouse model neoplastic cell neurotoxicity overexpression peripheral blood pre-clinical preclinical evaluation receptor response success therapeutic target transgene expression treatment response tumor

项目摘要

Project Summary Chimeric antigen receptor (CAR) T cell therapies are transforming clinical care of hematological malignancies; however, they have shown limited clinical success in treating solid tumors. Numerous efforts are underway to expand the use of CAR T cells for different cancer types, but their effectiveness in treating solid tumors have been limited by the fact that solid tumors are heterogenous; targeting a single antigen using CAR T cells typically results in tumor antigen escape, leading to relapse of the disease. Although systemic delivery of immunomodulators can potentiate anti-tumor responses, it can also lead to debilitating adverse events from on- target, off-tumor toxicity, cytokine release syndrome, and in some cases, life-threatening autoimmunity. By contrast, intratumoral administration of immunomodulators has been shown to reduce systemic exposure while improving efficacy of systemic therapies. Immunity against tumor antigens, resultant of epitope spreading after tumor cell killing, leads to a diversification of epitope specificity from the initial epitope – priming the endogenous immune system against larger pool of targets. This proposal seeks to use thermal sensitive CAR T cells, which traffic and infiltrate deep within tumors, to intratumorally produce bispecific T cell engagers (BTEs) and induce epitope spread by DC priming of endogenous anti-tumor T cells to develop robust immunity. Focused ultrasound (FUS) will be used to spatially deposit heat within heterogenous tumors and activate CAR T cells engineered with a thermal gene switch (TS) which allows for heat-triggered control of transgene expression in murine T cells. TS constructs are transcriptionally silent at body temperature (37°C) but after exposure to a short duration of heat (10 min. at 40–42°C), express transgenes to levels greater than 200-fold above basal levels. These studies will focus on BTEs targeting natural killer group 2, member D ligands (NKG2DL), which are stress-induced antigens highly expressed on tumor cells as well as on immunosuppressive cells. Preclinical evaluation will be performed in murine models of breast cancer in fully immunocompetent mice. This approach is expected to significantly enhance local CAR T cell activity against heterogenous tumors, while potentiating endogenous antitumor immunity. To assess this, epitope spread by DC mediated priming of the endogenous T cells will be investigated. Successful completion of the aims of this study is expected to elucidate mechanisms by which local BTE secretion by CAR T cells can prime endogenous T cell immunity.

项目总结