Innate Antiviral Signals for Cancer Immunotherapy

用于癌症免疫治疗的先天抗病毒信号

• 批准号: 9925289
• 负责人: Matthias Gromeier
• 金额: $ 35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/9925289
• 关键词: Agreement; Anatomy; Antigen-Presenting Cells; Antitumor Response; Antiviral Agents; 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; 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; outcome forecast; poliovirus receptor; prevent; progenitor; programs; receptor; response; systemic autoimmunity; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

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.

WHO IV级恶性胶质瘤是大多数癌症的标志，其中免疫治疗的功效是低的。 检查点阻断受到低突变负担和由免疫抑制引起的臭名昭著的免疫抑制的阻碍。 未参与的肿瘤微环境。为了克服这些障碍并实现成功的免疫治疗， 恶性神经胶质瘤（或其他“非免疫原性”癌症），新的方法必须能够免疫 参与肿瘤微环境（TME）以激发新的抗肿瘤免疫库。我们的项目是 重点关注脊髓灰质炎：鼻病毒嵌合体PVSRIPO，及其在脊髓灰质炎中引起炎症反应的能力。 TME。PVSRIPO在患者中进行单次对流增强肿瘤内输注后产生有希望的反应 复发性WHO IV级恶性胶质瘤它的目标是肿瘤细胞的感染和破坏凭借 其受体CD 155肿瘤抗原在这些细胞上的异位表达。然而，我们假设， PVSRIPO免疫治疗潜力的关键是脊髓灰质炎病毒对抗原呈递细胞的固有嗜性 （APCs），例如肿瘤相关巨噬细胞，以及对先天性抗病毒干扰素（IFN）的特殊抗性 反应PVSRIPO感染APC可促进亚致死性病毒增殖，引起严重的、持续的 I型IFN应答并刺激T细胞共刺激功能。人们普遍认为， APC中先天性抗病毒应答的无与伦比的刺激对于产生肿瘤抗原特异性抗病毒抗体是关键的。 抗肿瘤免疫与APC在自然脊髓灰质炎病毒感染中的作用一样，PVSRIPO的性质和程度 在体内肿瘤中与骨髓宿主细胞的相互作用是未知的。例如，允许的机制 慢性PVSRIPO复制，在APC中细胞毒性减弱--其IFN占主导地位的必要前奏 激活-保持模糊。本项目中提出的研究对临床至关重要。 PVSRIPO免疫疗法在恶性胶质瘤及其他肿瘤中的发展。因此，我们正在寻求 1）定义PVSRIPO翻译能力、细胞毒性和细胞毒性的分子基础， 巨噬细胞/骨髓细胞中的I型IFN诱导。我们将在人类骨髓源性 巨噬细胞，以机械地破译PVSRIPO与APC的独特关系; 2）解开 PVSRIPO在体内胶质瘤TME中重编程巨噬细胞/髓样细胞的潜力，并确定 巨噬细胞在PVSRIPO免疫治疗中的作用。我们将使用可移植的化学诱导-和 基因工程免疫活性小鼠胶质瘤模型，以研究肿瘤基质在 3）阐明PVSRIP 0对巨噬细胞/髓样细胞的靶向作用; 原代人胶质母细胞瘤外植体，并在体外检查促炎性重编程。我们将破译 胶质瘤患者新鲜、未分离的原代组织外植体对PVSRIPO感染的TME反应 并测量其克服T细胞抑制的潜力。