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

基本信息

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
项目类别：
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

项目摘要

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免疫检查点阻断（ICB）等免疫疗法在其他领域取得了成功。迄今为止，GBM 中的癌症尚未得到复制，可能需要对 GBM 进行有效的免疫治疗。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在这个重新提交的 R21 提案中，为指导和开发有效的未来临床试验提供治疗组合。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 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，已被用于我们之前发表的研究表明 BiA 可以治疗慢性粒细胞白血病和牛皮癣。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、系统地输送：静脉注射，它可以提高具有 GBM 的免疫活性小鼠的存活率。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，包括我们还发现 BiA/PPRX- 增加了 CD8+ T 细胞，并减少了促进肿瘤的巨噬细胞。第1701章 1701 证实 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，我们在目标 1 中提出确定最佳方案。在目标 2 中，我们将描述多种小鼠 GBM 模型中的剂量、生物分布、毒性和功效。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。