Newly identified potential therapeutic approach kills triple-negative breast cancer cells in pre-clinical study.
Findings suggests potential new area of focus for checkpoint blockade immunotherapy.
Triple-negative breast cancer (TNBC), a highly aggressive, relapse-prone cancer that accounts for one-fourth of all breast cancers, could be the focus of a new area of study for immune checkpoint blockade therapy. A team of researchers at The University of Texas MD Anderson Cancer Center revealed that in TNBC a cell process called glycosylation is required for PD-L1/PD1 molecules to interact and identified exactly how and why glycosylation is so crucial. Findings from the study were published in the Feb. 12 issue of Cancer Cell.
Immune checkpoint blockade therapy relies on connections between PD-L1 and its sister molecule, PD1, found on T-cell surfaces, allowing cancer cells to go undetected by the immune system. Blocking PD-L1 and PD-1 interaction has been the basis for successful immunotherapies already in use in other cancers.
Mien-Chie Hung, Ph.D.
"Glycosylation is a process that attaches portions of sugar molecules called moieties to the protein providing it fuel to grow and spread," said Mien-Chie Hung, Ph.D., chair of Molecular and Cellular Oncology. "Glycosylation of PD-L1 in tumor cells stabilizes PD-L1, but it is largely unknown whether sugar moiety by itself is required for binding to PD-1 to suppress anti-tumor immunity."
Hung's research group shed further light in this area through discovery of glycosylated PD-L1 (gPD-L1), and worked with STCube Pharmaceuticals, Inc. to develop anti-gPD-L1 antibodies that recognize this glycosylated form of PD-L1, killing tumor cells while not harming healthy ones.
To improve the therapeutic efficacy of anti-gPD-l1 antibody, the team linked a potent small molecule chemotherapy agent, called MMAE, to the anti-gPD-L1, creating a new antibody drug conjugate (ADC), called anti-gPD-L1-MMAE, which resulted in higher therapeutic efficacy in animal models. Hung believes the development of this glycosylated PD-L1 ADC (anti-gPD-L1-MMAE) may represent a new generation of immunotherapy that is more targeted with fewer adverse effects.
"We demonstrated that gPD-L1 is an excellent candidate for ADC as sugar moiety is critical for PD-L1's detrimental role in TNBC," said Hung. "Immune checkpoint blockade treatment options remains limited in TNBC, so identifying new immune checkpoint targets to improve upon current therapy is urgently needed."
MD Anderson study participants included: Chia-Wei Li, Ph.D.; Seung-Oe Lim, Ph.D.; Jun Yao, Ph.D.; Jong-Ho Cha, Ph.D.; Weiya Xia, M.D.; Li-Chuan Chan; Taewan Kim, Ph.D.; Shih-Shin Chang, Ph.D.; Heng-Huan Lee, Ph.D.; Chao-Kai Chou, Ph.D.; Jennifer Hsu, Ph.D.; Jung-Mao Hsu, Ph.D.; Hirohito Yamaguchi, D.V.M., Ph.D.; and Tzu-Hsuan Huang, Ph.D., all of the Department of Molecular and Cellular Oncology.
The study was funded by the National Institutes of Health (CCSG CA16672 and R21 CA193038); the Cancer Research Institute of Texas (RP160710); the National Breast Cancer Foundation, Inc.; the Breast Research Foundation (BRCF-17-069); the Patel Memorial Breast Cancer Endowment Fund; The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund; the Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE and MOST 105-2911-1-002-302); China Medical University Hospital Cancer Research Center of Excellence (MOHW106-TDU-B-212-144003); the Center for Biological Pathways; the Susan G. Komen for the Cure Postdoctoral Fellowship (PDF122311298); and the National Research Foundation of Korea (MSIP, NRF-2011-357-C00140 and2011-030001).