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.

项目摘要/摘要胰腺癌或胰腺癌（PC）是癌症相关死亡的第三主要原因美国。尽管最近的治疗方法最近取得了进步，包括手术，放射治疗，化学疗法和免疫疗法，5年的存活率低至9％。该项目的长期目标是为独立使用或标准使用PC开发一流，高效且可容忍的疗法化学和/或免疫检查点阻滞（ICB）治疗作为诱导和/或维持治疗。在PC患者中，TREM-1的过表达与生存率差有关，隐含的TREM-1作为新的目标。当前的TREM-1阻滞剂都试图阻止不确定配体与TREM-1的结合。减少在诊所发生失败的风险，我们开发了与配体无关的TREM-1抑制性肽GF9，可以是配制成巨噬细胞特异性脂蛋白肽络合物（LPC），以改善其半衰期和靶向。在第一阶段，我们表明：1）在抑制肿瘤生长并改善生存时，TREM-1封锁在PC Xenographictic中使用GF9-LPC与标准化学疗法一样有效：吉西他滨（GEM）+NAB-PACLITAXEL （PTX）组合和2）在GEM+NAB-PTX中添加GF9-LPC将肿瘤感知到化学疗法和三倍小鼠的存活率。从机械上讲，在PC Xenographictic中，GF9-LPC减少了与肿瘤相关的巨噬细胞（TAM）CSF1的浸润和血清水平。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可逆转免疫抑制并克服抗PDL1电阻。该项目的目的是进一步开发GF9疗法以作为指导/维护单独或进行一线标准化学治疗（GEM+NAB-PTX）和/或ICB（抗PD1/PDL1）。第二阶段的目的是：1）生成和测试合理设计的制造友好的GF9序列 - 基于有利的药代动力学曲线和高效率的基于基于的公式，并选择铅（Sub-aim - 制定评估以分析PK研究中血液中的GF9），2）测试铅与结合 PC的xenogrogroticon和Syngeneic小鼠模型中的GEM+NAB-PTX，3）测试铅与抗 - PC的合成小鼠模型中的PD1/PDL1，4）在非临床毒理学研究中测试铅。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。包括CSF-1在内的细胞因子将进行分析。后续IIB阶段将包括其他给药和组合（例如，辐射+GF9；抗CSF-1R+ GF9）方案，TOX，ADME，CMC和其他辅助研究。最终制造友好的产品将代表安全稳定的PC疗法。 Signablok的良好耐受性支持了其预期的安全长期治疗的健康，癌症和艺术小鼠基于GF9序列的公式。原型 Signablok的LPC在临床试验中是安全且耐受性的。 TREM-1使用胡椒LR12进行封锁 Signablok的顶级竞争对手（法国Inotrem）在健康和化粪池的受试者中是安全且耐受性的。