医学
流式细胞术
抗体
免疫疗法
细胞因子
肿瘤微环境
转化生长因子β
癌症研究
免疫系统
转化生长因子β信号通路
体内
转化生长因子
免疫学
药理学
内科学
生物
生物技术
作者
Xiaomei Li,Yi Ding,Ling Xiao,Rui Chen,Ying Qing,Qiu Hong Jiang,Yangchun Gao
标识
DOI:10.1200/jco.2020.38.15_suppl.e15200
摘要
e15200 Background: With the emergence of immunotherapy in recent years, therapeutic antibodies against programmed death 1 (PD1) and its ligand (PDL1) have proven to be a huge success in multiple cancer types. However, these robust responses only occur in a subset of patients. Identifying mechanisms of responses and resistance is key to improve outcomes and setup new treatment strategies. Transforming Growth Factor-beta (TGF-beta) is an immunosuppressive cytokine and overexpression of TGF-beta in the tumor microenvironment is proven to be a key element of resistance to anti-tumor response. We have developed a novel peptide HTPEP-001 which blocks TGF-beta signaling in both cellular and fibrosis animal models (ATS-2020 abstract). In this study, we explored the antitumor effect and mechanism of HTPEP-001 when administered together with anti-PD1 antibody in mice models. Methods: Animal models: 1. C57BL/6 mice were inoculated subcutaneously with 5*10 5 MC38 cells. 2. BALB/c mice were inoculated on the right mammary fat pad with 1*10 5 EMT-6 cells. Treatment groups: A. HTPEP-001 (60 mg/kg, intravenously, qd); B. isotype IgG; C. rat anti-mouse PD1 (10 mg/kg, intraperitoneally, twice a week); D. Coadminstration of HTPEP-001 and anti-PD1 (combo). Treatments were initiated 4-5 days after inoculation and lasted for 10 days. ELISA, immunofluorescence and flow cytometry analysis of dissected tumors were performed. Results: Compared to anti-PD1 group, mice treated with both HTPEP-001 and anti-PD1 exhibited additional reductions in tumor size and 13% higher inhibition of tumor growth (59% in Anti-PD-1 vs 72% in combo) in MC38 model. In the EMT6 model, coadministration of HTPEP-001 and anti-PD1 also showed additional reduction in tumor burdens. Coadmistration of HTPEPE-001 and anti-PD-1 significantly decreased active TGF-beta 1 and phosphorylated Smads expression in tumors in both MC38 and EMT6 models. Furthermore, immunofluorescence and flow cytometry analysis of CD8 + lymphocytes in tumor mass revealed markedly elevated number of cytotoxic tumor infiltrating lymphocytes in combo group compared to HTPEP-001 and anti-PD1 groups. Conclusions: This study showed that HTPEP-001 enhanced the anti-tumor activity of anti-PD1 via suppressing TGF-beta signaling and promoting infiltration of cytotoxic lymphocytes in two syngeneic tumor models. We will continue to develop HTPEP-001 as an add-on therapy to checkpoint inhibitors with a goal to improve the outcomes of current immunotherapy.
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