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

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GF 9， 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GF 9-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GF 9-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，GF 9-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GF 9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GF 9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PD 1/PDL 1）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GF 9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GF 9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PD 1/PDL 1，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+GF 9;抗CSF-1 R + GF 9）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。其预期的安全性得到了SignaBlok良好耐受性的支持 通过长期治疗的健康、癌症和关节炎小鼠的基于GF 9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LR 12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。

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.