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.

项目摘要嵌合抗原受体（CAR）T细胞疗法正在转化血液恶性肿瘤的临床护理；但是，他们在治疗实体瘤方面显示出有限的临床成功。正在进行许多努力将汽车T细胞用于不同癌症类型的使用，但是它们在治疗实体瘤中的有效性具有由于实体瘤是异质的事实，受到限制。通常使用CAR T细胞靶向单个抗原导致肿瘤抗原逃生，导致疾病缓解。虽然全身交付免疫调节剂可以潜在的抗肿瘤反应，也可能导致衰弱的不良事件靶标，肿瘤毒性，细胞因子释放综合征以及在某些情况下会威胁生命的自身免疫性。经过对比，已显示免疫调节剂的肿瘤内给药可降低全身暴露，而提高全身疗法的效率。对肿瘤抗原的免疫力，由表位扩散后的肿瘤抗原。肿瘤细胞杀死，导致表位特异性从初始表位多样化 - 启动内源性免疫系统针对更大的目标池。该提案试图使用热敏感的汽车T细胞，肿瘤内的交通和浸润深处在肿瘤内产生双特异性T细胞探手（BTE）和影响表位通过直流启动内源性抗肿瘤T细胞的传播，从而发展出强大的免疫力。集中的超声（FUS）将用于空间沉积在异质肿瘤中并激活工程的CAR T细胞使用热基因开关（TS），可以通过热触发鼠T细胞中转化表达的控制。 TS构建体在体温下（37°C）在转录中保持沉默，但暴露于短时间内热量（在40–42°C下为10分钟），将转基因表达为高于基本水平200倍的水平。这些研究将重点介绍针对自然杀手级第2组，成员D配体（NKG2DL）的BTE，它们是应力诱导的在肿瘤细胞以及免疫抑制细胞上高度表达的抗原。临床前评估将是在完全免疫能力的小鼠的鼠类乳腺癌模型中进行。这种方法有望显着增强了针对异质肿瘤的局部CAR T细胞活性，同时增强内源性抗肿瘤免疫。为了评估这一点，表位通过直流介导的内源性T细胞的启动扩散将是调查。预计成功完成这项研究的目标将阐明本地的机制 CAR T细胞的BTE分泌可以促进内源性T细胞免疫。