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Innate Antiviral Signals for Cancer Immunotherapy

用于癌症免疫治疗的先天抗病毒信号

基本信息

批准号：
10395967
负责人：
Matthias Gromeier
金额：
$ 35万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395967
关键词：
Agreement Anatomy Antigen-Presenting Cells Antitumor Response Antiviral Response Automobile Driving Cell Proliferation Cells Characteristics Chemicals Chimera organism Chronic Classification Combination immunotherapy Competence Convection Dendritic Cells Dose Ectopic Expression Effector Cell Engineering Exhibits Genetic Engineering Glioblastoma Glioma Grant Heterogeneity Human Human poliovirus Immune Immune Cell Suppression Immunocompetent Immunologics Immunosuppression Immunotherapy In Vitro Incidence Infection Inflammation Inflammatory Inflammatory Response Infusion procedures Interferon Type I Interferon Type II Interferons Interleukin-12 Investigation Malignant - descriptor Malignant Glioma Malignant Neoplasms Measures Modeling Molecular Mus Mutation Myelogenous Myeloid Cells Nature Newly Diagnosed Operative Surgical Procedures Patients Pattern recognition receptor Phase I Clinical Trials Phenotype Poliomyelitis Primary Brain Neoplasms Prognosis Recombinants Recurrence Resistance Rhinovirus Role Signal Transduction Stimulus T-Lymphocyte TNF gene Tissues Toxic effect Transgenic Model Translations Transplantation Tropism Tumor Antigens Tumor Immunity Tumor-associated macrophages Viral Virus angiogenesis base cancer immunotherapy clinical application clinical development cytotoxicity exhaustion immune activation immune checkpoint blockade in vivo insight macrophage mouse model neoplastic cell neutrophil novel novel strategies poliovirus receptor prevent progenitor programs receptor response systemic autoimmunity tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

WHO grade IV malignant glioma is emblematic for a majority of cancers, where the efficacy of immune checkpoint blockade is impeded by a low mutational burden and notorious immunosuppression incited by a non-engaged tumor microenvironment. To overcome these hurdles and achieve successful immunotherapy of malignant glioma (or other `non-immunogenic' cancers), novel approaches must be capable of immunologically engaging the tumor microenvironment (TME) to instigate new antitumor immune repertoire. Our project is focused on the polio:rhinovirus chimera PVSRIPO, and its capacity to elicit inflammatory responses in the TME. PVSRIPO yields promising responses after single, convection-enhanced intratumoral infusion in patients with recurrent WHO grade IV malignant glioma. It targets neoplastic cells for infection and destruction by virtue of ectopic expression of its receptor, the CD155 tumor antigen, on such cells. We hypothesize, however, that the key to PVSRIPO's immunotherapy potential is poliovirus' inherent tropism for antigen presenting cells (APCs), e.g. tumor-associated macrophages, and a peculiar resistance to the innate antiviral interferon (IFN) response. PVSRIPO infection of APCs elicits sublethal viral propagation that provokes profound, sustained type I IFN responses and stimulates T cell co-stimulating functions. There is broad agreement that the unparalleled stimulus of the innate antiviral response in APCs is pivotal for generating tumor antigen-specific antitumor immunity. As with the role of APCs in natural poliovirus infection, the nature and extent of PVSRIPO interactions with myeloid host cells in tumors in vivo are unknown. For example, the mechanisms permitting chronic PVSRIPO replication with subdued cytotoxicity in APCs -necessary preludes to their IFN-dominant activation- remain obscure. The investigations proposed in this project are of utmost importance for the clinical development of PVSRIPO immunotherapy in malignant gliomas and beyond. Therefore, we are pursuing the following Specific Aims: 1) Define the molecular basis for PVSRIPO translation competency, cytotoxicity and type I IFN induction in macrophages/myeloid cells. We will perform studies in human myeloid-derived macrophages to mechanistically decipher the unique relationship of PVSRIPO with APCs; 2) Unravel PVSRIPO's potential for reprogramming macrophages/myeloid cells in the glioma TME in vivo and determine the role of macrophages in PVSRIPO immunotherapy. We will use transplantable chemically-induced- and genetically-engineered immunocompetent mouse glioma models to investigate the role of tumor stroma in PVSRIPO-instigated antitumor immunity; 3) Elucidate PVSRIPO targeting of macrophages/myeloid cells in primary human glioblastoma explants and examine proinflammatory reprogramming in vitro. We will decipher the TME response to PVSRIPO infection in fresh, non-dissociated primary tissue explants from glioma patients and measure its potential in overcoming T cell suppression.

世卫组织IV级恶性胶质瘤是大多数癌症的象征，其中免疫疗法的疗效如何