MEK Inhibitor Augments Antitumor Activity of B7-H3-Redirected Bispecific Antibody

Frontiers in Oncology

卷:10

Wenhao Guo¹  Liangxue Zhou²  Jianguo Xu²  Xin Tang²  Hui Yang³  Kunhong Zhong⁴  Aiping Tong⁴  Yunyu Feng⁴  Hongjian Li⁴  Yating Hu⁴  Gang Guo⁴  Cheng Huang⁴  Zongliang Zhang⁴  Zeng Wang⁴ 

[1] Department of Abdominal Oncology, West China Medical School, West China Hospital, Sichuan University, Chengdu, China;

[2] Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China;

[3] Department of Otolaryngology, Head and Neck Surgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China;

[4] State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China;

关键词: trametinib;    B7-H3;    immunotherapy;    bispecific antibody;    non-small-cell lung cancer;    bladder cancer;   

DOI  :  10.3389/fonc.2020.01527

来源: DOAJ

【 摘 要 】

Targeting cancer antigens by T cell-engaging bispecific antibody (BiAb) or chimeric antigen receptor T cell therapy has achieved successes in hematological cancers, but attempts to use it to fight solid cancers have been disappointing, in part due to antigen escape. MEK inhibitor had limited activity as a single agent, but enhanced antitumor activity when combined with other therapies, such as targeted drugs or immunotherapy agents. This study aimed to analyze the expression of B7-H3 in non-small-cell lung cancer (NSCLC) and bladder cancer (BC) and to evaluate the combinatorial antitumor effect of B7-H3 × CD3 BiAb with MEK inhibitor trametinib. We found B7-H3 was highly expressed in NSCLC and BC compared with normal samples and its increased expression was associated with poor prognosis. Treatment with trametinib alone could induce apoptosis in tumor cell, while has no effect on T cell proliferation, and a noticeable elevation of B7-H3 expression in tumor cells was also observed following treatment. B7-H3 × CD3 BiAb specifically and efficiently redirected their cytotoxicity against B7-H3 overexpressing tumor cells both in vitro and in xenograft mouse models. While trametinib treatment alone affected tumor growth, the combined therapy increased T cell infiltration and significantly suppressed tumor growth. Together, these data suggest that combination therapy with B7-H3 × CD3 BiAb and MEK inhibitor may serve as a new therapeutic strategy in the future clinical practice for the treatment of NSCLC and BC.

【 授权许可】

Unknown