Enhanced Viro-Immunotherapy for Breast Cancer Brain Metastasis

乳腺癌脑转移的增强病毒免疫疗法

• 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
• 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

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.

项目摘要/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 选项。尽管乳腺癌（BC）患者的存活率有所提高，但BCBM的事件为 随着诊断成像和全身疗法的最新进展以及长期生存率的近期增长 这些患者不可接受，紧急要求采取新的干预措施。溶瘤疱疹单纯疱疹病毒-1 （OHSV）治疗是FDA批准的美国黑色素瘤和 有条件地用于日本的胶质母细胞瘤。但是，累积的临床数据表明OHSV治疗 非常微弱的影响系统性抗肿瘤免疫响应，通常被免疫抑制作用抵消 肿瘤微环境（TME）。这是抗病毒抗性的机械识别是最大化的关键 它的治疗效率。在BCBM中，我们观察到OHSV治疗诱导胰岛素样生长因子2（IGF2） 表达和分泌，在TME中维持促炎性中性粒细胞，极化变化为促进 肿瘤中性粒细胞，阻碍病毒繁殖并阻止强大自适应的发展 抗肿瘤免疫反应。此外，我们发现OHSV疗法浸润的嗜中性粒细胞会诱导 中性粒细胞外陷阱（净）形成（也称为“ Netosis”），阻碍了治疗效率 维罗免疫疗法。该应用程序的总体目标是确定临床差的最终原因 癌症患者对OHSV疗法的反应，并开发出一种更有效的新型病毒免疫疗法 无法治愈的BCBM。我们的目标是通过破译OHSV-背后的抗病毒抗性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抑制和净的治疗益处 OHSV治疗的降解。为了妥协OHSV诱导的IGF2及其信号通路，我们生成了一个 新颖的IGF2扫描OHSV（OHSV-D11MT），并在与 放射疗法也受到IGF2，中性粒细胞浸润和Netosis的阻碍。我们也生成了 抗肌动蛋白抗DNase1表达OHSV（OHSV-HADNASE1）以降解网络以增强病毒 传播并获得浸润的细胞毒性淋巴细胞。为了检验这些假设，我们将研究 IGF2在病毒清除和肿瘤进展中的矛盾作用（AIM 1），评估治疗潜力 IGF2扫描OHSV-D11MT与放射疗法结合（AIM 2），并评估临床前效率 净减轻OHSV-HADNASE1（AIM 3）。预计这项拟议的研究的成功完成将揭幕 OHSV治疗引起的中性粒细胞浸润和净形成的作用，并阐明了为什么OHSV治疗 不像预期的那样成功的病毒免疫疗法。因此，它将加速OHSV的翻译 治疗BCBM患者的有效且改进的治疗方式。