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)是临床面临的一大挑战，因其对治疗的反应较差。 选择。尽管乳腺癌(BC)患者的生存率有所提高，但BCBM的发病率是 随着诊断成像和系统治疗的最新进展， 这些患者的水平低得令人无法接受，迫切需要新的干预措施。溶瘤单纯疱疹病毒-1 OHSV疗法是美国FDA批准的治疗黑色素瘤的最先进的病毒疗法， 在日本，胶质母细胞瘤是有条件的。然而，越来越多的临床数据显示，OHSV治疗 非常弱的诱导全身抗肿瘤免疫反应，通常被免疫抑制所抵消 肿瘤微环境。因此，抗病毒抗性的机制鉴定是最大限度地提高抗病毒力的关键 它的治疗效果。在BCBM中，我们观察到OHSV治疗诱导胰岛素样生长因子2(IGF2) TME中促炎性中性粒细胞的表达和分泌，以及极化向促炎性中性粒细胞的转变 肿瘤中性粒细胞，阻碍了病毒的繁殖和发展，具有很强的适应性 抗肿瘤免疫反应。此外，我们还发现OHSV治疗中的中性粒细胞渗入可诱导 中性粒细胞胞外陷阱(Net)的形成(也称为NET病)，阻碍了对 病毒免疫疗法。这个应用程序的首要目标是找出临床效果差的最终原因 癌症患者对OHSV治疗的反应，并开发一种更有效的新型病毒免疫疗法 不治之症。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，并评价IGF2抑制和Net的治疗效果 OHSV治疗的退化。为了折衷OHSV诱导的IGF2及其信号通路，我们产生了一个 新的IGF2-扫描OHSV(OHSV-D11mt)，并将探讨联合应用的治疗效果 放射治疗也受到IGF2、中性粒细胞渗入和网织红细胞增多的阻碍。我们还生成了 肌动蛋白抗性DNase1表达的OHSV(oHSV-haDNase1)降解Net以增强病毒 增殖和获得渗入的细胞毒性淋巴细胞。为了检验这些假设，我们将调查 IGF2在病毒清除和肿瘤进展中的相互矛盾的作用(目标1)，评估其治疗潜力 IGF2-结合放射治疗清除OHSV-D11mt(目标2)，并评估其临床前疗效 网络缓解oHSV-haDNase1(目标3)。这项拟议研究的成功完成预计将揭开面纱 OHSV治疗诱导中性粒细胞浸润和网状形成的作用及其原因的解释 没有像预期的那样成功地进行病毒免疫治疗。因此，它将加速OHSV的翻译 为BCBM患者提供一种有效和改进的治疗方式。