In principle, anti-PD-1 and anti-PD-L1 work differently than anti-CTLA-4 blockers due to different ligand-receptor interactions, he said. However, in practice, they show similar efficacy and toxicity. Anti-CTLA-4 promotes T cell priming by antigen-presenting cells in the lymph nodes. Anti-PD-1 or anti-PD-L1 promote the affector functions of T cells in tumors. “T-reg cells play a somewhat tricky role—they are a subset of T cells that suppress the immune response. In humans, the role of anti-CTLA-4 and T-regs are still controversial,” he said.
Explore This IssueNovember 2018
Anti-PD-L1 is a negative co-stimulator, said Dr. Koh. PD-L1 expression is in response to IFN-γ expressed by T cells. This is an example of adaptive resistance: Tumor cells express PD-L1 to protect them from the T cells’ attack, and anti-PD-1 or anti-PD-L1 therapies rescue the T cells from this adaptive resistance.
Researchers must explore the extrinsic control of PD-L1 expression and the intrinsic control of the PD-L1 pathway, said Dr. Koh. Various carcinogenesis-related pathways also trigger PD-L1 expression, and its expression in tumors does not always guarantee the efficacy of anti-PD-1 or anti-PD-L1 therapies. “We have to know the biomarkers to overcome the resistance to checkpoint blockade. We have to know: What is the issue with PD-L1 as a biomarker?” he said.
In general, checkpoint blockade works better for high-frequency, somatic mutation tumors, said Dr. Koh. Due to diverse mechanisms of innate or adaptive resistance, some patients may not respond well to immunotherapy. Researchers must learn more about the role of IFN-γ on cancer cell growth, and the phenomenon of T-cell exhaustion, he said.
“Despite unprecedented efficacy, many patients fail to respond, or they may acquire resistance to the drugs over time,” said Dr. Koh. “There is an urgent need to identify the mechanisms of resistance to predict outcomes and identify targets for combination therapy.”
Combination with Radiation
Would combining immunotherapy and radiation overcome resistance? Recent research is optimistic, said John B. Sunwoo, MD, Edward C. and Amy H. Sewall Professor of Medicine and director of head and neck cancer research at Stanford University.
Immunotherapy includes initiators (ipilimumab) and amplifiers (pembrolizumab or nivolumab) of the immune response. “What are the effects of radiation on the immune response? Radiation is also an initiator,” he said. A 2017 murine study by researchers at the University of Colorado Denver showed that radiation can make the tumor more sensitive to PD-L1 therapy, leading to enhanced tumor control and improved survival (Oncoimmunology. 2017;6(10):e1356153). Several ongoing trials are exploring combination therapy with checkpoint inhibitors and radiation.