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.

项目概要嵌合抗原受体 (CAR) T 细胞疗法正在改变血液恶性肿瘤的临床护理；然而，它们在治疗实体瘤方面所取得的临床成功有限，目前正在进行许多努力。扩大 CAR T 细胞在不同癌症类型中的使用，但其治疗实体瘤的有效性受到实体瘤异质性的限制；通常使用 CAR T 细胞靶向单一抗原；导致肿瘤抗原逃逸，导致疾病复发。免疫调节剂可以增强抗肿瘤反应，但也可能导致衰弱性不良事件靶标、肿瘤外毒性、细胞因子释放综合征，以及在某些情况下危及生命的自身免疫。相比之下，免疫调节剂的瘤内给药已被证明可以减少全身暴露，同时提高全身治疗的功效，这是由于表位扩散后产生的。肿瘤细胞杀伤，导致表位特异性从初始表位开始多样化——启动内源性该提案旨在使用热敏感 CAR T 细胞来对抗更大的靶标。运输并渗透到肿瘤深处，在肿瘤内产生双特异性 T 细胞接合剂 (BTE) 并诱导通过内源性抗肿瘤 T 细胞的 DC 启动来传播表位，以产生强大的免疫功能。 (FUS) 将用于在异质肿瘤内空间沉积热量并激活工程化的 CAR T 细胞带有热基因开关 (TS)，可通过热触发控制小鼠 T 细胞中的转基因表达。 TS 构建体在体温 (37°C) 下转录沉默，但在暴露于短时间的加热（40–42°C 10 分钟），将转基因表达水平高于基础水平 200 倍以上。将重点关注针对自然杀伤组 2、成员 D 配体 (NKG2DL) 的 BTE，这些配体是应激诱导的肿瘤细胞和免疫抑制细胞上高表达的抗原将进行临床前评估。这种方法有望在具有完全免疫能力的小鼠乳腺癌小鼠模型中进行。显着增强局部 CAR T 细胞针对异质肿瘤的活性，同时增强内源性为了评估这一点，将通过 DC 介导的内源性 T 细胞的启动来扩展表位。调查的成功完成本研究的目标预计将阐明当地的机制。 CAR T 细胞分泌的 BTE 可以启动内源性 T 细胞免疫。