Preclinical assessment of efficacy and tumor microenvironment alterations by PPRX-1701 in glioblastoma

PPRX-1701 在胶质母细胞瘤中的疗效和肿瘤微环境改变的临床前评估

• 批准号: 10578085
• 负责人: Sean Edward Lawler
• 金额: $ 22.95万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-03 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578085
• 关键词: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Aryl Hydrocarbon Receptor; Biodistribution; Biological Availability; Biological Process; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cell Line; Cells; Chemicals; Chinese; Chinese Traditional Medicine; Chronic Myeloid Leukemia; Clinical Trials; Coculture Techniques; Combination immunotherapy; Combined Modality Therapy; Cytometry; Data; Development; Dose; Drug Kinetics; Enzymes; Excision; Formulation; Future; Glioblastoma; Goals; Heterogeneity; Human; Immune; Immune system; Immunocompetent; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Interferons; Intracranial Neoplasms; Intravenous; Invaded; Kynurenine; Macrophage; Malignant Neoplasms; Malignant neoplasm of brain; Medical; Modeling; Molecular; Molecular Biology; Mus; Natural Products; Nature; Operative Surgical Procedures; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphoproteins; Physiological; Plants; Proliferating; Psoriasis; Publishing; Refractory; Safety; Solubility; Suspensions; Testing; Therapeutic; Toxic effect; Tryptophan; Tryptophan 2,3 Dioxygenase; Tumor Immunity; Tumor Promotion; Xenograft Model; Xenograft procedure; angiogenesis; cancer therapy; cancer type; chemoradiation; clinical development; clinical translation; copolymer; design; efficacy evaluation; experimental study; immune checkpoint blockade; improved; in vivo; indigo dye; indirubin; intravenous administration; intravenous injection; irradiation; kinase inhibitor; melanoma; mouse model; nanoparticle; nanopolymer; novel; novel therapeutic intervention; pre-clinical; pre-clinical assessment; preclinical study; rapid growth; refractory cancer; response; standard of care; success; transcriptome sequencing; translational therapeutics; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Project Summary/Abstract The malignant brain tumor glioblastoma (GBM) remains incurable with little improvement in patient outcomes over many decades. The success of immunotherapies such as immune checkpoint blockade (ICB) in other cancers has not been replicated so far in GBM. Effective application of immunotherapy for GBM may need combination therapies based on detailed understanding of molecular biology and immunosuppressive mechanisms in the tumor microenvironment (TME), as well as preclinical studies of rational synergistic therapeutic combinations to inform and develop effective future clinical trials. In this resubmitted R21 proposal we will build on preliminary data showing inhibition of expression of IDO1 and altered TME in GBM by the drug PPRX-1701, a newly developed bioavailable formulation of the indirubin derivative 6-bromoindirubin-3'- acetoxime (BiA), to understand its mechanism of action and provide preclinical data which may support its use in human GBM patients. BiA is a chemically modified form of indirubin, a natural product derived from the indigo plant which is an active component of anti-inflammatory Traditional Chinese Medicines, which has been used to treat chronic myelogenous leukemia and psoriasis. Our previously published studies showed that BiA could prolong survival of human GBM xenografts in mice via effects on invasion, proliferation and angiogenesis. However, we did not examine the potential immunological effects of BiA, and the further development of this concept was hampered by poor solubility which limits applicability in patients. PPRX-1701 is a BiA/copolymer nanoparticle suspension that can be efficiently systemically delivered safely by intravenous injection, where it increases survival in GBM-bearing immunocompetent mice. Our initial studies of PPRX-1701 in murine GBM show targeting of intracranial tumors and alterations in TME composition including increased CD8+ T cells, and decreased tumor promoting macrophages. We have also shown that BiA/PPRX- 1701 potently blocks induction of the immunosuppressive enzyme IDO1 by interferon- We therefore hypothesize that BiA/PPRX-1701 promotes alterations in the TME as a result of inhibition of immunosuppressive pathways, increasing animal survival and anti-tumor immunity. Here we propose in Aim 1 to determine optimal dosing, biodistribution, toxicity and efficacy in multiple murine GBM models. In Aim 2 we will characterize in detail the molecular and cellular alterations associated with PPRX-1701 treatment in vivo, and test combination immunotherapies with a view to clinical translation if data supports. The experiments described here will rapidly establish mechanism and applicability of PPRX-1701 for GBM treatment, and provide a platform for future detailed studies and informed clinical trials.

项目摘要/摘要 恶性脑肿瘤胶质母细胞瘤（GBM）仍然无法治愈，患者预后几乎没有改善 数十年来。免疫疗法的成功，例如免疫切除术（ICB） 到目前为止，癌症尚未在GBM中复制。有效应用免疫疗法可能需要 基于对分子生物学和免疫抑制的详细了解的组合疗法 肿瘤微环境（TME）的机制，以及理性协同的临床前研究 治疗组合，以告知和开发有效的未来临床试验。在此重新提交的R21建议中 我们将建立在初步数据的基础上，显示抑制IDO1表达和通过药物改变GBM的TME PPRX-1701，一种新开发的Indirubin衍生物6-溴inifubin-3'-的生物利用公式 乙酰氧米（BIA），了解其作用机理并提供临床前数据，以支持其使用 在人类GBM患者中。 BIA是一种化学修饰的Intirubin，是一种衍生自靛蓝的天然产物 植物是抗炎传统中药的活跃成分，该药物已用于 治疗慢性骨髓性白血病和牛皮癣。我们先前发表的研究表明，BIA可以 小鼠中人类GBM异种移植物的延长生存期通过对侵袭，增殖和血管生成的影响。 但是，我们没有检查BIA的潜在免疫学影响，并进一步发展 概念受到限制限制患者适用性的溶解度的阻碍。 PPRX-1701是BIA/共聚物纳米颗粒悬浮液，可以通过 静脉注射，在该注射中增加了具有GBM的免疫能力小鼠的存活率。我们对 鼠GBM中的PPRX-1701显示颅内肿瘤的靶向和TME组成的改变 增加了CD8+ T细胞，并增加了促进巨噬细胞的肿瘤。我们还表明BIA/PPRX- 1701可能会阻止Interferon-的免疫抑制酶IDO1的诱导 假设BIA/PPRX-1701促进了由于免疫抑制作用而促进TME的改变 途径，增加动物存活率和抗肿瘤免疫力。在这里，我们在AIM 1中建议确定最佳 多种鼠GBM模型中的剂量，生物分布，毒性和效率。在AIM 2中，我们将描述 详细说明与PPRX-1701治疗相关的分子和细胞改变，并进行测试组合 免疫疗法，以临床翻译的观点，如果数据支持。 此处描述的实验将迅速建立PPRX-1701的机制和适用性 治疗，并为将来的详细研究和知情临床试验提供平台。