Abstract LB-193: Preclinical antitumor activity of a first-in-class TREM-1 inhibitory peptide GF9 as monotherapy and in combo with chemotherapy or radiation

Abstract

Abstract Despite significant advances in cancer care, effective treatments are still lacking for non-small cell lung cancer (NSCLC), glioblastoma multiforme (GBM) and pancreatic cancer (PC) that are among the most lethal cancer types, necessitating the development of novel therapies. In addition, an estimated 99% of GBM drugs in development fail to cross the blood-brain barrier (BBB), further complicating the treatment of this cancer. In recent years, a growing line of evidence indicates that blockade of triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, may represent a transformative therapeutic approach for these tumors. Considering the uncertainty related to TREM-1 ligands, we developed a first-in-class non-toxic TREM-1 inhibitory peptide GF9 that employs a ligand-independent mechanism of TREM-1 blockade. In order to extend GF9 half-life and enhance its targeting, we used an epitope-based rational design to construct self-assembling brain-permeable macrophage-specific lipopeptide complexes (LPC) capable of targeted delivery of GF9 in vivo. Confocal studies in rats and rabbits confirm the capability of GF9 formulated into LPC (GF9-LPC) to cross the BBB. In this study, we evaluated antitumor activity of GF9-LPC alone and in combination with chemotherapy and radiation therapy in xenograft and orthotopic mouse cancer models. In experimental NSCLC and PC, depending on the xenograft, 2.5 mg/kg GF9-LPC as monotherapy suppresses tumor growth and extends survival duration as effectively as first-line standard chemotherapy regimen: 20 mg/kg paclitaxel (PTX) and 100 mg/kg gemcitabine (GEM) in combination with 10 mg/kg nanoparticle albumin-bound PTX (nab-PTX) for NSCLC and PC, respectively. In PANC-1 xenograft tumor model, the adding of 2.5 mg/kg GF9-LPC to 100 mg/kg GEM in combination with 10 mg/kg nab-PTX triples the survival rate for tumor-bearing animals as compared to chemotherapy-treated mice. The tumor growth delay persists after treatment is halted, thus highlighting the long lasting anticancer effects. The lack of body weight loss observed in the long term-treated mice indicates the safety of GF9-LPC therapy. Mechanistically, TREM-1 blockade significantly reduces intratumoral macrophage infiltration (up to 60%) and serum levels of interleukin (IL)-1α, IL-6 and macrophage colony-stimulating factor (M-CSF, also known as CSF-1). In orthotopic GBM, systemically administered 2.5 mg/kg GF9-LPC significantly increases the survival of GL261 tumor-bearing animals in combination with radiation, but has no significant benefit in the absence of radiation. In summary, this multi-indication study is the first to demonstrate potent antitumor efficacy of TREM-1 blockade using GF9 as monotherapy and especially when added to standard chemo- or radiation therapy. Citation Format: Daniel J. Mark, Zu T. Shen, Rosamaria Ruggieri, Marc H. Symons, Alexander B. Sigalov. Preclinical antitumor activity of a first-in-class TREM-1 inhibitory peptide GF9 as monotherapy and in combo with chemotherapy or radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-193.