Anti-PD-L1 checkpoint inhibitors: Decoding the mystery

July 24, 2019 | by City of Hope

An extensive study conducted by City of Hope experts Michael Caligiuri, M.D., president of City of Hope National Medical Center and the Deana and Steve Campbell Physician-in-Chief Distinguished Chair, and Jianhua Yu, Ph.D., a professor in the Department of Hematology & Hematopoietic Cell Transplantation unveiled a medical mystery. It was not well understood why anti-PD-L1 monoclonal antibodies (mAb), also known as checkpoint inhibitors, are still effective in fighting tumors that lack PD-L1 receptors on their cells. This discovery is believed to provide one reason why.     
By leveraging advanced techniques, including CRISPR-Cas9, RNA microarray for gene profiling and cytotoxicity assays, this study provides evidence to shed the old belief that PD-L1 expression is only associated with T cells binding and deactivation. Our experts analyzed the AKT signaling pathways of myeloid leukemia cells. As a result, they discovered that NK cells become activated upon encountering NK-susceptible tumor cells. This not only increases secretion of cytokine and cytolytic granules, but also increases the immune cells’ effectiveness. The interaction is upregulated by the addition of anti-PD-L1 mAb agents, creating a positive feedback loop that mobilizes NK cell anti-tumor functions.
To examine the correlation of this discovery to clinical outcomes, 79 patients with acute myeloid leukemia (AML) were examined. Results reveal those who achieved complete remission out of all responders (66%) had significantly higher percentages of PD-L1+ NK cells in their peripheral blood samples at remission compared to nonresponders. Taken together, this data suggests that activated NK cells with expression of PD-L1 may possess powerful anti-tumor activity.
Activating NK cells for the destruction of cancer cells may transform immunotherapy approaches. Yu asserts that “using checkpoint inhibitors for NK cells with PD-L1 expression can lead to stronger anti-cancer activity, providing us with another powerful therapy against even more cancers.”     
Based on this discovery, City of Hope is working on launching a series of clinical trials for patients with NK-susceptible tumors in various cancer types. These trials will focus on AML initially, then expand to include patients with lung cancer. Full details on this study are published in AACR journal Cancer Discovery. Learn more now about the important implications of this discovery in the press release.
 
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