A research team in the University of Macau’s (UM) Faculty of Health Sciences (FHS), led by FHS Assistant Professor Zhao Qi, designed two novel immunotherapeutic antibody drugs targeting an immune checkpoint B7-H3. Two antibody drugs can be used to promote the anti-tumour immunity of the patient’s own immune system against non-small cell lung cancer (NSCLC). The study has been published in the high-impact academic journal Journal of Hematology & Oncology.
Adoptive immunotherapy that uses effector lymphocytes expressing tumour-specific antibodies is a promising approach to cancer treatment. To facilitate immune cell responses, Prof Zhao and his research team designed two modalities, CART and bispecific killer cell engager (BiKE), using single-chain variable fragments (scFvs) to redirect cytotoxic lymphocytes against tumour cells. Their studies have laid the groundwork for further development of two therapeutic agents in preclinical and clinical studies.
NSCLC is a major subtype of epithelial lung cancer and accounts for a majority of lung cancer cases. Despite considerable progress in the development of immune checkpoint inhibitors, particularly the encouraging therapy of anti-PD-1 antibodies, a portion of NSCLC patients still remain generally resistant to these therapies. The UM team discovered that the B7-H3 molecule was highly associated with the long-term survival rate of NSCLC patients. While B7-H3 protein is expressed at low levels in most normal tissues, it is aberrantly expressed during differentiated stages of NSCLC. Their studies suggest that B7-H3 may serve as an attractive target for immunotherapy.
The modalities, CART and bispecific killer cell engager (BiKE), use single-chain variable fragments (scFvs) to redirect cytotoxic lymphocytes against tumour cells. CART is a genetically engineered T cell that expresses the anti-B7-H3 antibody on the surface of the T cell. The BiKE is designed as a ‘bridge’ between tumour cells and NK cells. One arm binds to the CD16 receptor of NK, and the other arm binds to the B7-H7 antigen of tumour cells. CART cells effectively inhibited NSCLC tumourigenesis. B7-H3 redirection promoted highly specific T-cell infiltration into tumours. Additionally, NK cell activity could be specially triggered by B7-H3/CD16 BiKE through direct CD16 signalling, resulting in significant increase in NK cell activation and target cell death. Furthermore, they found that anti-B7-H3 blockade might alter tumour glucose metabolism via the reactive oxygen species-mediated pathway.
FHS’s PhD students, Liu Jie and Yang Shuo, are the co-first authors, and Prof Zhao Qi is the corresponding author. FHS professors Kathy Luo Qian, Chen Guokai, and Di Lijun made important contributions to this study. The study was funded by the Science and Technology Development Fund (FDCT), Macao SAR (file number: 131/2016/A3 and 0015/2018/A1), National Key R&D Programme of China (file number: 2019YFA0904400), Guangzhou Municipal Science and Technology Bureau (file number：201807010004), and UM (file number: MYRG2019-00069-FHS and SRG2016-00082-FHS). The full-text version of the related paper can be viewed at: https://doi.org/10.1186/s13045-020-01024-8
Targeting B7-H3 via CART and BiKE augments antitumour response of cytotoxic lymphocytes
Yang Shuo (1st row, 2nd from left), Zhao Qi (1st row, 4th from left), and Liu Jie (1st row, 2nd from right)