Enhanced Viro-Immunotherapy for Breast Cancer Brain Metastasis

乳腺癌脑转移的增强病毒免疫疗法

基本信息

批准号：
10803696
负责人：
Ji Young Yoo
金额：
$ 50.02万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2023-09-22 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10803696
关键词：
Acceleration Actins Acyclovir Address Antiviral resistance Breast Cancer Patient Cancer Patient Clinical Clinical Data Complex Development Diagnostic Imaging FDA approved Future Generations Glioblastoma Goals Hyperactivity Immune Evasion Immunity Immunotherapy In Vitro Incidence Infiltration Inflammatory Injectable Insulin-Like Growth Factor II Intervention Japan Lymphocyte Malignant Neoplasms Mediating Metastatic malignant neoplasm to brain Microglia Modality Modeling Mus Neutrophil Infiltration Outcome Patients Quality of life Radiation therapy Research Resistance Role Safety Signal Pathway Survival Rate Systemic Therapy T-Cell Activation T-Lymphocyte Testing Therapeutic Time Translations Treatment Efficacy Tumor Immunity Viral Virotherapy Virus Virus Replication advanced breast cancer anti-tumor immune response cancer cell cancer type clinical application cytotoxic extracellular immunotherapeutic virotherapy improved in vivo inhibitor malignant breast neoplasm melanoma neoplastic cell neutrophil novel novel therapeutic intervention oncolytic herpes simplex virus pre-clinical pre-clinical assessment preclinical efficacy prevent resistance mechanism response synergism tumor tumor heterogeneity tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Breast cancer brain metastasis (BCBM) is a major clinical challenge due to their poor response to therapeutic options. Although the survival rate of breast cancer (BC) patients has improved, the incidence of BCBM is increasing with recent advance in diagnostic imaging and systemic therapy, and long-term survival rates for these patients are unacceptably low, urgently calling for new interventions. Oncolytic herpes simplex virus-1 (oHSV) therapy is the most advanced virotherapy as approved by FDA for melanoma in the U.S. and conditionally for glioblastoma in Japan. However, accumulating clinical data is revealing that oHSV treatment very weakly induces a systemic anti-tumor immune response which is often offset by the immunosuppressive tumor microenvironment (TME). Thus, mechanistic identification of the anti-viral resistance is a key to maximize its therapeutic efficacy. In BCBM, we observed that oHSV therapy induces insulin-like growth factor 2 (IGF2) expression and secretion, sustaining pro-inflammatory neutrophils in the TME and polarization change to pro- tumoral neutrophils, hampering the virus propagation and discouraging the development of a strong adaptive anti-tumoral immune response. Additionally, we found that infiltrated neutrophils by oHSV therapy induces neutrophil extracellular trap (NET) formation (also called “NETosis”), hampering the therapeutic efficiency of Viro-Immunotherapy. The overarching goal of this application is to identify the ultimate cause of the poor clinical response of cancer patients to oHSV therapy, and develop a more effective novel viral immunotherapy for incurable BCBM. We aim to achieve our goal by deciphering anti-viral resistance mechanism behind oHSV- induced IGF2/microglia/neutrophil axis, and evaluating therapeutic benefit of IGF2 inhibition and NET degradation on oHSV therapy. To compromise oHSV-induced IGF2 and its signaling pathways, we generated a novel IGF2-scavanging oHSV (oHSV-D11mt) and will investigate the therapeutic benefit when combined with radiation therapy, which has also been hindered by IGF2, neutrophil infiltration and NETosis. We also generated actin resistant DNase1-expressing oHSV (oHSV-haDNase1) to degrade the NETs for enhanced virus propagation and access to infiltrating cytotoxic lymphocytes. To test these hypotheses, we will investigate the contradictory roles of IGF2 in virus clearance and tumor progression (Aim 1), evaluate therapeutic potential of IGF2-scavenging oHSV-D11mt in combination with radiotherapy (Aim 2), and assess the preclinical efficacy of NET-mitigating oHSV-haDNase1 (Aim 3). The successful completion of this proposed study is expected to unveil the role of neutrophil infiltration and NET formation induced by oHSV therapy, and elucidate why oHSV therapy was not as successful as viral immunotherapy as expected. Therefore, it will accelerate the translation of oHSV therapy into an efficient and improved treatment modality for the patients with BCBM.

项目概要/摘要乳腺癌脑转移（BCBM）是一个重大的临床挑战，因为它们对治疗的反应不佳尽管乳腺癌（BC）患者的生存率有所提高，但 BCBM 的发生率却很高。随着诊断成像和全身治疗的最新进展以及长期生存率的增加这些患者的感染率低得令人无法接受，迫切需要新的溶瘤单纯疱疹病毒-1 干预措施。 (oHSV) 疗法是美国 FDA 批准用于治疗黑色素瘤的最先进的病毒疗法然而，积累的临床数据表明，oHSV 治疗在日本是有条件的。非常微弱地诱导全身性抗肿瘤免疫反应，该反应通常被免疫抑制所抵消因此，抗病毒耐药性的机制识别是最大化的关键。在 BCBM 中，我们观察到 oHSV 疗法可诱导胰岛素样生长因子 2 (IGF2)。表达和分泌，维持 TME 中的促炎性中性粒细胞和极化转变为促炎性中性粒细胞肿瘤中性粒细胞，阻碍病毒繁殖并阻碍强适应性的发展此外，我们发现 oHSV 治疗可诱导浸润的中性粒细胞。中性粒细胞胞外陷阱（NET）的形成（也称为“NETosis”），阻碍了治疗效率该应用的首要目标是确定临床表现不佳的最终原因。癌症患者对 oHSV 治疗的反应，并开发更有效的新型病毒免疫疗法我们的目标是通过破译 oHSV- 背后的抗病毒耐药机制来实现我们的目标。诱导 IGF2/小胶质细胞/中性粒细胞轴，并评估 IGF2 抑制和 NET 的治疗益处为了损害 oHSV 诱导的 IGF2 及其信号通路，我们生成了一个新型 IGF2 清除 oHSV (oHSV-D11mt) 并将研究与放射治疗也受到 IGF2、中性粒细胞浸润和 NETosis 的阻碍。表达肌动蛋白抗性 DNase1 的 oHSV (oHSV-haDNase1) 可降解 NET 以获得增强病毒为了检验这些假设，我们将研究细胞毒性淋巴细胞的增殖和获取。 IGF2 在病毒清除和肿瘤进展中的矛盾作用（目标 1），评估 IGF2 的治疗潜力 IGF2 清除 oHSV-D11mt 联合放疗（目标 2），并评估临床前疗效 NET 缓解 oHSV-haDNase1（目标 3）预计这项研究的成功完成将揭开面纱。 oHSV 治疗诱导中性粒细胞浸润和 NET 形成的作用，并阐明 oHSV 治疗的原因并没有像预期的那样成功，因此，它将加速oHSV的转化。治疗成为 BCBM 患者有效且改进的治疗方式。