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.

项目概要/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 几十年来。免疫疗法（例如免疫检查点阻断（ICB））在其他领域的成功 迄今为止，癌症尚未在 GBM 中复制。 GBM 免疫疗法的有效应用可能需要 基于对分子生物学和免疫抑制的详细了解的联合疗法 肿瘤微环境（TME）的机制，以及合理协同的临床前研究 治疗组合，以指导和开发有效的未来临床试验。在这份重新提交的 R21 提案中 我们将基于显示该药物抑制 IDO1 表达并改变 GBM 中 TME 的初步数据 PPRX-1701，一种新开发的靛玉红衍生物 6-bromoindirubin-3'- 的生物可利用制剂 乙酰肟 (BiA)，了解其作用机制并提供可能支持其使用的临床前数据 在人类 GBM 患者中。 BiA 是靛玉红的化学修饰形式，靛玉红是一种从靛蓝中提取的天然产物 植物是抗炎中药的活性成分，已被用于 治疗慢性粒细胞白血病和牛皮癣。我们之前发表的研究表明 BiA 可以 通过影响侵袭、增殖和血管生成，延长小鼠体内人类 GBM 异种移植物的存活。 然而，我们并没有研究 BiA 的潜在免疫学作用，以及这种药物的进一步发展。 这一概念因溶解度差而受到阻碍，从而限制了患者的适用性。 PPRX-1701 是一种 BiA/共聚物纳米粒子悬浮液，可以通过以下方式有效、安全地系统输送： 静脉注射，可提高携带 GBM 的免疫活性小鼠的存活率。我们的初步研究 小鼠 GBM 中的 PPRX-1701 显示出颅内肿瘤的靶向性和 TME 成分的改变，包括 CD8+ T 细胞增加，促肿瘤巨噬细胞减少。我们还表明 BiA/PPRX- 第1701章 1701 假设 BiA/PPRX-1701 由于抑制免疫抑制而促进 TME 的改变 途径，提高动物存活率和抗肿瘤免疫力。在这里，我们在目标 1 中建议确定最优 多种小鼠 GBM 模型中的剂量、生物分布、毒性和功效。在目标 2 中，我们将描述 详细介绍与 PPRX-1701 体内治疗相关的分子和细胞变化，以及测试组合 如果数据支持的话，免疫疗法将着眼于临床转化。 这里描述的实验将快速建立 PPRX-1701 对于 GBM 的机制和适用性 治疗，并为未来的详细研究和知情临床试验提供平台。