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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.

项目总结/文摘