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

项目摘要/摘要 胰腺癌，或胰腺癌(PC)，是#年癌症相关死亡的第三大原因 美国。尽管目前的治疗方法取得了进展，包括手术、放射治疗、化疗- 而免疫治疗，5年存活率低至9%。这个项目的长期目标是 开发一流、高效和耐受性良好的PC治疗方法，可单独使用或与标准药物一起使用 化疗和/或免疫检查点阻断(ICB)治疗，如诱导和/或维持治疗。 在PC患者中，TREM-1的过度表达与生存不良相关，提示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配体(S)与TREM-1的结合。减少 在临床失败风险方面，我们开发了一种配体非依赖性的TREM-1抑制肽GF9，它可以 制成巨噬细胞特异性脂肽复合体(LPC)，以改善其半衰期和靶向性。 在第一阶段，我们发现：1)在抑制肿瘤生长和提高存活率方面，TREM-1阻断 在PC异种移植中使用GF9-LPC与标准化疗方案一样有效：吉西他滨(GEM)+NaB-紫杉醇 (PTX)组合，以及2)在GEM+NaB-PTX中加入GF9-LPC使肿瘤对化疗和三联化疗增敏 小鼠存活率。从机制上讲，在PC异种移植中，GF9-LPC减少了肿瘤相关巨噬细胞 ()CSF1的浸润和血清水平。正如其他人所表明的，在患有肝细胞癌的小鼠中， GF9阻断TREM-1+TAMS可逆转免疫抑制，克服抗PDL1耐药。 该项目的目标是进一步开发用于PC的GF9疗法，用于诱导/维持 单独治疗或一线标准化疗(GEM+NaB-PTX)和/或ICB(抗PD1/PDL1)。 第二阶段的目标是：1)生成和测试合理设计的制造友好型GF9序列- 具有良好药代动力学曲线和体内高效的基础剂型和选择的先导 (子目标-在PK研究中开发一种分析血液中GF9的分析方法)，2)结合 GEM+NaB-PTX在异种移植和同基因小鼠PC模型中的应用，3)联合检测铅和抗-PTX PD1/PDL1在同基因小鼠PC模型中的应用，以及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的浸润以及 血管生成、肿瘤细胞增殖和死亡。将分析包括脑脊液-1在内的细胞因子。 后续的IIb阶段将包括其他用药和联合用药(例如，放射+GF9；抗-CSF-1R+ 方案、TOX、ADME、CMC和其他支持IND的研究。最终制造友好型产品将 代表安全稳定的PC治疗。其预期的安全性得到了SignaBlok良好耐受性的支持 长期治疗的健康、癌症和关节炎小鼠基于GF9序列的配方。的原型 SignaBlok的LPC在临床试验中是安全和耐受性良好的。多肽LR12阻断TREM-1的实验研究 SignaBlok的头号竞争对手(法国的Inotrem)是安全的，在健康和败血症患者中耐受性良好。

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.