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

• 批准号: 9902597
• 负责人: Alexander B Sigalov
• 金额: $ 79.96万
• 依托单位: SIGNABLOK, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902597
• 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; 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

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.

项目概要/摘要 胰腺癌或胰腺癌 (PC) 是癌症相关死亡的第三大原因 美国。尽管目前的治疗方法包括手术、放射治疗、化疗等方面取得了进展， 而免疫疗法，5年生存率低至9%。该项目的长期目标是 开发一种一流的、高效且耐受性良好的 PC 疗法，可单独使用或与标准一起使用 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 的过度表达与较差的生存率相关，这表明 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配体与 TREM-1 的结合。减少 为了避免临床失败的风险，我们开发了一种配体独立的 TREM-1 抑制肽 GF9，它可以 配制为巨噬细胞特异性脂肽复合物（LPC），以提高其半衰期和靶向性。 在第一阶段，我们表明：1) 在抑制肿瘤生长和提高生存率方面，TREM-1 阻断 在 PC 异种移植中使用 GF9-LPC 与标准化疗一样有效：吉西他滨 (GEM)+白蛋白结合型紫杉醇 (PTX) 组合，以及 2) 在 GEM+nab-PTX 中添加 GF9-LPC 可使肿瘤对化疗和三联体敏感 小鼠的存活率。从机制上讲，在 PC 异种移植物中，GF9-LPC 减少肿瘤相关巨噬细胞 (TAM) 浸润和 CSF1 的血清水平。正如其他人所表明的，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 耐药性。 该项目的目标是进一步开发 GF9 治疗 PC 的诱导/维持疗法 单独治疗或与一线标准化疗（GEM+nab-PTX）和/或 ICB（抗 PD1/PDL1）联合治疗。 第二阶段的目标是：1）生成并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的基于制剂，并选择先导药物 （子目标 – 开发一种方法来分析 PK 研究中血液中的 GF9），2) 结合测试先导物 GEM+nab-PTX 在 PC 的异种移植和同基因小鼠模型中，3) 测试先导物与抗- PD1/PDL1在PC同基因小鼠模型中的应用，4)在非临床毒理学研究中测试领先地位。 将进行组织学/IHC 研究来分析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。 后续 IIb 期将包括其他给药和组合（例如放射+GF9；抗 CSF-1R+ GF9) 方案、TOX、ADME、CMC 和其他 IND 支持研究。最终制造友好的产品将 代表了安全稳定的PC疗法。 SignaBlok 的良好耐受性支持了其预期的安全性 由长期治疗的健康小鼠、癌症小鼠和关节炎小鼠开发的基于 GF9 序列的制剂。原型 SignaBlok 的 LPC 在临床试验中是安全且耐受性良好的。使用肽 LR12 阻断 TREM-1 SignaBlok 的顶级竞争对手（法国 Inotrem）在健康和脓毒症受试者中是安全的且耐受性良好。