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First-in-class TREM-1 inhibitors in combination therapy for pancreatic cancer

用于胰腺癌联合治疗的一流 TREM-1 抑制剂

基本信息

批准号：
10024061
负责人：
Alexander B Sigalov
金额：
$ 119.82万
依托单位：
SIGNABLOK, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-21 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10024061
关键词：
Animal Cancer Model Animals Arthritis Base Sequence Binding Biological Assay Biophysics Blood CSF1 gene Cancer Etiology Cancer Patient Canis familiaris Cell Death Cell Proliferation Cells Cessation of life Clinic Clinical Trials Combined Modality Therapy Complex Data Development Disease Dose Drug Kinetics Drug Targeting Failure Formulation France Goals Half-Life Histology Human Immunosuppression Immunotherapy In Vitro Infiltration Lead Life Ligands Macrophage Colony-Stimulating Factor Maintenance Therapy Malignant Neoplasms Malignant neoplasm of pancreas Mus Neoadjuvant Therapy Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Operative Surgical Procedures PD-1/PD-L1 Paclitaxel Pancreatic carcinoma Pathology Patients Peptides Phase Primary carcinoma of the liver cells Radiation Radiation therapy Rattus Regimen Research Resistance Risk Safety Serum Structure Survival Rate Testing Therapeutic Toxicology Tumor Volume Tumor-associated macrophages United States Xenograft procedure angiogenesis anti-PD-1 anti-PD-L1 anti-PD-L1 therapy base cancer therapy cancer type cytokine design follow-up gemcitabine immune checkpoint blockade improved in vivo inhibitor/antagonist innovation macrophage mouse model neoplastic cell novel novel therapeutics overexpression pancreatic cancer model pancreatic cancer patients protein aminoacid sequence prototype reduce symptoms septic targeted treatment tumor tumor growth

项目摘要

Project Summary/Abstract Carcinoma of the pancreas, or pancreatic cancer (PC), is the third leading cause of cancer-related death in the US. Despite recent advances in the current treatments that include surgery, radiation therapy, chemo- and immunotherapy, the 5-year survival rate is as low as 9%. The long-term goal of this project is to develop a first-in-class, efficient and well tolerable therapy for PC to be used standalone or with standard chemo- and/or immune checkpoint blockade (ICB) treatments as induction and/or maintenance therapy. In PC patients, overexpression of TREM-1 correlates with poor survival, implicating TREM-1 as a new target. Current TREM-1 blockers all attempt to block binding of uncertain ligand(s) to TREM-1. To reduce risk of failure in the clinic, we developed a ligand-independent TREM-1 inhibitory peptide GF9 that can be formulated into macrophage-specific lipopeptide complexes (LPC) to improve its half-life and targeting. In Phase I, we showed that: 1) In suppressing tumor growth and improving survival, TREM-1 blockade using GF9-LPC in PC xenografts is as effective as a standard chemo: gemcitabine (GEM)+nab-paclitaxel (PTX) combo, and 2) addition of GF9-LPC to GEM+nab-PTX sensitizes the tumor to chemo and triples survival rate of mice. Mechanistically, in PC xenografts, GF9-LPC reduces tumor-associated macrophage (TAM) infiltration and serum level of CSF1. As shown by others, in mice with hepatocellular carcinoma, blocking TREM-1+ TAMs by GF9 reverses immunosuppression and overcomes anti-PDL1 resistance. The goal of this project is to further develop GF9 therapy for PC to be used as an induction/maintenance therapy alone or with first-line standard chemo treatments (GEM+nab-PTX) and/or ICB (anti-PD1/PDL1). Phase II aims are to: 1) generate and test rationally designed manufacturing friendly GF9 sequence- based formulations with favorable pharmacokinetic profile and high efficacy in vivo and select the lead (sub-aim – develop an assay to analyze GF9 in blood in PK studies), 2) test the lead in combination with GEM+nab-PTX in xenograft and syngeneic mouse models of PC, 3) test the lead in combination with anti- PD1/PDL1 in syngeneic mouse models of PC, and 4) test the lead in the non-clinical toxicology studies. Histology/IHC studies will be performed to analyze intratumoral macrophage infiltration as well as angiogenesis, tumor cell proliferation and death. Cytokines including CSF-1 will be analyzed. Follow-up Phase IIb will include other administration and combination (eg, radiation+GF9; anti-CSF-1R+ GF9) regimen, TOX, ADME, CMC and other IND-enabling studies. Final manufacturing friendly product will represent safe and stable PC therapy. Its anticipated safety is supported by good tolerability of SignaBlok's GF9 sequence-based formulations by long term-treated healthy, cancer and arthritic mice. Prototypes of SignaBlok's LPC were safe and well tolerated in clinical trials. TREM-1 blockade using peptide LR12 by SignaBlok's top competitor (Inotrem, France) was safe and well tolerated in healthy and septic subjects.

项目总结/摘要胰腺癌或胰腺癌（PC）是美国癌症相关死亡的第三大原因。美方尽管目前的治疗方法，包括手术，放射治疗，化疗，免疫治疗的5年生存率低至9%。该项目的长期目标是开发一流的、有效的、耐受性良好的PC治疗方法，可单独使用或与标准治疗方法联合使用化疗和/或免疫检查点阻断（ICB）治疗作为诱导和/或维持治疗。在PC患者中，TREM-1的过表达与不良生存相关，暗示TREM-1是一种新的目标目前的TREM-1阻断剂都试图阻断不确定的配体与TREM-1的结合。减少为了降低临床失败的风险，我们开发了一种配体非依赖性TREM-1抑制肽GF9，将其配制成巨噬细胞特异性脂肽复合物（LPC）以改善其半衰期和靶向。在第一阶段，我们发现：1）在抑制肿瘤生长和提高生存率，TREM-1阻断，在PC异种移植物中使用GF9-LPC与标准化疗一样有效：吉西他滨（GEM）+nab-紫杉醇 (PTX)组合，以及2）向GEM + nab-PTX中添加GF9-LPC使肿瘤对化疗敏感，并且三倍小鼠的存活率。从机制上讲，在PC异种移植物中，GF9-LPC减少了肿瘤相关巨噬细胞 (TAM)浸润和血清CSF 1水平。如其他人所示，在患有肝细胞癌的小鼠中，通过GF9阻断TREM-1 + TAM逆转免疫抑制并克服抗PDL 1抗性。本项目的目标是进一步开发用于PC的GF9疗法，作为诱导/维持治疗。单独治疗或与一线标准化疗治疗（GEM + nab-PTX）和/或ICB（抗PD1/PDL1）联合治疗。第二阶段的目标是：1）生成和测试合理设计的制造友好的GF9序列- 具有良好的药代动力学特征和体内高效性的基于制剂，（子目标-开发一种分析PK研究中血液中GF9的测定法），2）测试铅与 GEM + nab-PTX在PC的异种移植物和同基因小鼠模型中，3）测试与抗- 在PC的同基因小鼠模型中检测PD1/PDL1，以及4）在非临床毒理学研究中检测铅。将进行组织学/IHC研究以分析肿瘤内巨噬细胞浸润以及血管生成、肿瘤细胞增殖和死亡。将分析包括CSF-1在内的细胞因子。 IIb期随访将包括其他给药和联合给药（例如，放疗+GF9;抗CSF-1R + GF9）方案、TOX、ADME、CMC和其他IND使能研究。最终制造友好产品将代表安全和稳定的PC治疗。SignaBlok的良好耐受性支持了其预期的安全性通过长期治疗的健康、癌症和关节炎小鼠的基于GF9序列的制剂。的原型 SignaBlok的LPC在临床试验中安全且耐受性良好。通过使用肽LR12阻断TREM-1 SignaBlok的主要竞争药物（Inotrem，法国）在健康和脓毒症受试者中安全且耐受性良好。