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。免疫检查点阻断(ICB)等免疫疗法在其他领域的成功 到目前为止，癌症还没有在GBM中复制。GBM免疫治疗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治疗 肿瘤微环境(TME)的机制，以及合理协同作用的临床前研究 治疗组合，以提供信息并开发有效的未来临床试验。在重新提交的R21建议书中 我们将建立在初步数据的基础上，显示药物抑制GBM中IDO1的表达和改变TME PPRX-1701，一种新开发的靛玉红衍生物6-溴-靛玉红-3‘-生物可用制剂-- 乙酮肟(BIA)，以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是蓝宝石的一种化学修饰形式，它是从蓝宝石中提取的天然产物 植物是抗炎中药的有效成分，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 通过对侵袭、增殖和血管生成的影响延长小鼠人GBM移植瘤的存活。 然而，我们没有研究BIA的潜在免疫学影响，以及它的进一步发展 概念受到溶解性差的阻碍，这限制了其在患者中的适用性。 PPRX-1701是一种BIA/共聚纳米颗粒悬浮剂，可通过以下方式高效、系统、安全地递送 静脉注射，可提高携带GBM免疫活性小鼠的存活率。我们的初步研究 PPRX-1701在小鼠GBM中显示靶向颅内肿瘤和TME成分的变化，包括 CD8+T细胞增加，促肿瘤巨噬细胞减少。我们还表明，BIA/PPRX- 有效阻断干扰素-对免疫抑制酶IDO_1的诱导 假设BIA/PPRX-1701通过抑制免疫抑制促进TME的改变 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模型的剂量、生物分布、毒性和有效性。在目标2中，我们将在 详细说明与体内PPRX-1701治疗相关的分子和细胞变化，以及测试组合 免疫疗法，以期在数据支持的情况下临床翻译。 本文描述的实验将迅速建立PPRX-1701对GBM的作用机理和适用性 并为未来的详细研究和知情的临床试验提供了一个平台。