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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-项目四：