Project 4:Targeting M2-like Macrophages and MDSC with Myelolytic-Virotherapy

项目 4：利用溶髓病毒疗法靶向 M2 样巨噬细胞和 MDSC

基本信息

批准号：
10885263
负责人：
TIMOTHY P CRIPE
金额：
$ 36.69万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10885263
关键词：
Adoptive Transfer CXCL10 gene Cancer Etiology Cancer Vaccines Cell Therapy Cells Cellular immunotherapy Chemotactic Factors Childhood Clinical Combined Modality Therapy Data Development Ewings sarcoma FDA approved Flow Cytometry Gene Delivery Gene Expression Genomics Glioma Human Immune Immunocompetent Immunologic Monitoring Immunosuppression Immunotherapy Impairment Inflammatory Liposomes Macrophage Malignant Childhood Neoplasm Measures Mediating Modeling Monoclonal Antibody Therapy Myeloid-derived suppressor cells NK cell therapy Natural Killer Cells Neuroblastoma Oncolytic Oncolytic viruses Phagocytes Phagocytosis Phenotype Population Relapse Research Personnel Resource Sharing Rhabdomyosarcoma Role Shapes Signal Transduction Solid Neoplasm Stress Suppressor-Effector T-Lymphocytes T cell clonality T cell receptor repertoire sequencing T-Lymphocyte Testing Treatment Efficacy Tumor-associated macrophages Tumor-infiltrating immune cells Vaccines Virotherapy Virus Virus Diseases Work Xenograft Model Xenograft procedure bisphosphonate cancer cell cancer immunotherapy cancer regression cancer therapy cancer type chemokine chemotherapy chimeric antigen receptor T cells cytotoxic exhaustion gain of function herpes virotherapy innate immune mechanisms loss of function member nanodiamond neoplastic cell neutrophil new technology osteosarcoma pediatric patients permissiveness recruit synergism therapeutic target time of flight mass spectrometry trafficking transcriptomics tumor tumor microenvironment tumor xenograft tumor-immune system interactions vaccine strategy

项目摘要

Abstract - Project 4: Cure rates for pediatric patients with relapsed or metastatic solid tumors remain unacceptably low. Cancer immunotherapies hold great promise, but scores of disappointing studies highlight our relative ignorance in understanding the immunosuppressive microenvironment within solid tumors. Because of their central role in mediating immunosuppression, tumor associated macrophages (TAMs), typically “polarized” to a so-called M2- like immunosuppressive phenotype, and myeloid-derived suppressor cells (MDSC), are thought to be important therapeutic targets. We have found a clinically viable strategy that simultaneously reduces TAMs/MDSC (we dub “myelolytic”) and polarizes the microenvironment (via oncolytic virus infection), resulting in significant antitumor efficacy. We hypothesize that targeting TAM and MDSC by combining “myelolytic” therapies with pro- inflammatory therapies activates innate antitumor mechanisms that cause cancer regressions and reshapes the solid tumor microenvironment to be more permissive to cellular immunotherapies. In aim 1, we will determine the mechanism(s) by which combined myelolytic-virotherapy drives tumor regressions. We will use novel technologies such as fluorescent nanodiamonds to determine effects on innate immune cell phagocytosis of tumor cells. We will utilize the Genomics & Immune Monitoring Shared Resource Core B directed by Dr. Elaine Mardis to conduct flow cytometry with time-of-flight mass spectrometry and single cell transcriptomics to determine the effects on immune cell composition and polarization. We will also utilize gain- and loss-of-function approaches to determine if loss of MDSC are critical for enabling tumor regressions with myelolytic-virotherapy. We will also test combination therapies in xenograft and immunocompetent models of other cancer types to confirm its generalizability (osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma). In aim 2, we will determine the effects of myelolytic-virotherapy on T cell-mediated immunotherapies. We will examine the effect of myelolysis alone and combined with virotherapy on the efficacy of antitumor T cells in a T cell exhaustion setting and with CAR-T cells (with Project 1 Leader Dean Lee and co- investigator Ruoning Wang, PI-DDN U01 member). We will work with Core B to examine the effects on T cell clonality using TCR sequencing. In aim 3, we will determine whether combined myelolytic-virotherapy enhances the efficacy of NK-based cellular therapies. We will work with Project 1 Leader Dean Lee and Project 2 Leader Mitch Cairo to study the effects on adoptive NK and CAR-NK cell therapy. Overall, with this project we will further elucidate, test and develop strategies to modulate the tumor microenvironment to facilitate innate immune cells as cancer therapy. Our findings may be applicable across a broad panel of pediatric cancer types and thus fits well into the aims of the Pediatric Immunotherapy Discovery and Development Network.

摘要 - 项目4：小儿继电器或转移性实体瘤的儿科患者的治疗率仍然不可接受。癌症免疫疗法具有巨大的希望，但是许多令人失望的研究强调了我们的相对无知了解实体瘤内的免疫抑制微环境。因为他们在中心作用介导免疫抑制，肿瘤相关巨噬细胞（TAM），通常“极化”到所谓的M2-- 像免疫抑制表型和髓样衍生的抑制细胞（MDSC）一样，被认为很重要治疗靶标。我们发现了一种临床上可行的策略，可以简单地减少TAM/MDSC（我们配音 “髓分析”），并对微环境（通过溶瘤病毒感染）偏振，从而导致明显功效。我们假设通过将“髓分析”疗法与促进剂相结合的靶向TAM和MDSC 炎症疗法激活了引起癌症回归和的先天抗肿瘤机制重塑实体微环境更允许细胞免疫疗法。 1，我们将确定合并骨髓病毒疗法驱动肿瘤的机制回归。我们将使用新颖的技术（例如荧光纳米符号）来确定对先天性的影响肿瘤细胞的免疫细胞吞噬作用。我们将利用基因组学和免疫监控共享资源由Mardis博士指导的核心B通过飞行时间质谱和单一进行流式细胞术细胞转录组学确定对免疫细胞组成和极化的影响。我们还将利用获得功能丧失方法，以确定MDSC损失对于实现肿瘤回归至关重要与髓分解性疗法一起使用。我们还将测试纳学和免疫能力模型中的组合疗法在其他癌症类型中确认其普遍性（骨肉瘤，尤因肉瘤，横纹肌肉瘤，成神经细胞瘤）。在AIM 2中，我们将确定髓分解性疗法对T细胞介导的影响免疫疗法。我们将仅检查单独髓溶解的作用，并与病毒疗法结合对有效性在T细胞耗尽设置和CAR-T细胞中的抗肿瘤T细胞（项目1领导者）研究人员Ruoning Wang，Pi-DDN U01成员）。我们将与Core B一起检查对T细胞的影响使用TCR测序的克隆性。在AIM 3中，我们将确定是否合并骨髓性疗法提高基于NK的细胞疗法的效率。我们将与项目1负责人迪恩·李（Dean Lee）合作，项目2领导者米奇·开罗（Mitch Cairo）研究对自适应NK和CAR-NK细胞疗法的影响。总体而言，这是如此项目我们将进一步阐明，测试和开发策略，以调节肿瘤微环境以促进先天免疫细胞作为癌症治疗。我们的发现可能适用于大量小儿癌症类型，因此非常适合小儿免疫疗法发现和开发网络的目标。