Anti-PD-1 combination therapy the way forward
Combination therapy for programmed death-1 (PD-1) blockade using mitochondrial activators, especially peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), may be the next focus of cancer research, says an expert.
Just like the role of penicillin in starting the era of antibiotics, the discovery of PD-1 is the starting point for immunotherapy in cancer. This is just the beginning and there will be more discovery to come, said Professor Tasuku Honjo, of the Department of Immunology and Genomic Medicine, Kyoto University Graduate School of Medicine, Japan. Honjo is the first scientist to identify and clone PD-1.
PD-1 is a checkpoint protein on T-cells that functions as an ‘off switch’ to stop the cells from attacking other cells in the body. It is only able to function if it is attached to programmed death-ligand 1 (PD-L1). In some cancers, the cancer cells have substantial amounts of PD-L1 to help them evade immune attack. Immunotherapy drugs can target either PD-1 or PD-L1 and increase the immune response against cancer cells. [Annu Rev Immunol 2008;26:677–704]
Immunotherapy using PD-1 blockade has improved the outcomes for cancer patients. However, more research is necessary to improve the efficacy in patients who are less sensitive to the treatment. Currently, there are numerous on-going studies on immunotherapy-based combination therapy for cancer. This is because there are endless possibilities for combination therapy involving immune checkpoint inhibitors, said Honjo. Possible combinations would include combining with currently established treatments, low dose anti-cancer drugs or low dose irradiation. There are also the possibilities of combination with blockade of other negative regulators such as LAG3 and TIM3, and combination with mitochondrial activators, he continued.
Mitochondrial activators are an especially viable candidate for combination therapy with anti-PD-1 drugs, said Honjo. They are also good markers to assess the effectiveness of immunotherapy. Tumour reactive cytotoxic T-cells in draining lymph nodes (DLN) have been shown to have elevated mitochondrial mass and more reactive oxygen species (ROS). The formation of ROS synergized the tumoricidal activity of PD-1 blockade by expansion of cytotoxic T-cells in both the DLN and tumor.
These T-cells carry the activation of mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK) and other transcription factors such as PGC-1α and T-bet, he said. Alone, the direct activators of mTOR, AMPK, or PGC-1α do not have any effects on tumor growth. However, when used in combination with PD-1 blockade therapy, they had a synergistic effect. As such, Honjo believes this will pave the way for the development of new combinatorial therapies with anti-PD-1.