MEK Inhibitor Augments Antitumor Activity of B7-H3-Redirected Bispecific Antibody
Hongjian Li1, Cheng Huang1, Zongliang Zhang1
1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Abstract:
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.
Insights
Combining B7-H3 × CD3 bispecific antibodies with MEK inhibitor trametinib shows promise for treating non-small-cell lung cancer and bladder cancer. This combination therapy enhances T cell activity and significantly suppresses tumor growth.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Bispecific antibody (BiAb) and chimeric antigen receptor T cell therapies show success in hematological cancers but struggle with solid tumors due to antigen escape.
- MEK inhibitors have limited single-agent activity but enhance antitumor effects when combined with other therapies.
- B7-H3 is a potential target in solid tumors, with high expression in non-small-cell lung cancer (NSCLC) and bladder cancer (BC) associated with poor prognosis.
Purpose of the Study:
- To analyze B7-H3 expression in NSCLC and BC.
- To evaluate the combined antitumor effect of B7-H3 × CD3 BiAb and the MEK inhibitor trametinib.
Main Methods:
- Analysis of B7-H3 expression in NSCLC and BC tissues.
- In vitro and in vivo evaluation of trametinib monotherapy and B7-H3 × CD3 BiAb monotherapy.
- Assessment of combination therapy effects on tumor cell apoptosis, T cell proliferation, T cell infiltration, and tumor growth in xenograft mouse models.
Main Results:
- B7-H3 is highly expressed in NSCLC and BC, correlating with poor prognosis.
- Trametinib monotherapy induced tumor cell apoptosis and increased B7-H3 expression but did not affect T cell proliferation.
- B7-H3 × CD3 BiAb demonstrated specific cytotoxicity against B7-H3-expressing tumor cells.
- Combination therapy significantly suppressed tumor growth, increased T cell infiltration, and showed enhanced antitumor activity compared to monotherapy.
Conclusions:
- Combined therapy with B7-H3 × CD3 BiAb and trametinib demonstrates significant antitumor efficacy in preclinical models of NSCLC and BC.
- This combination strategy warrants further investigation as a potential therapeutic approach for NSCLC and BC.
- Targeting B7-H3 in conjunction with MEK inhibition offers a promising new avenue for solid tumor treatment.
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