Researchers are focusing on several major areas to improve cancer immunotherapy. Now, a team at Kyoto University report they have developed a synthetic molecule that can provide energy to anticancer immune cells, increasing their numbers and improving their longevity.

Their findings are published in the journal Cell Chemical Biology in a paper titled, “Targeted epigenetic induction of mitochondrial biogenesis enhances antitumor immunity in mouse model.”

“Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of programmed cell death protein 1 (PD-1) blockade, leading to better cancer treatment,” the researchers wrote.

“Although epigenetic drugs showed potential in combination therapy, the lack of sequence specificity is a major concern. Here, we identify and develop a DNA-based epigenetic activator with tri-arginine vector called EnPGC-1 that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1α/β), a regulator of mitochondrial biogenesis.”

Cancer cells express molecules that can target a receptor to inactivate tumor-fighting T cells. “Therapeutics that block the immunosuppressive molecule, called PD-L1, from binding to the T cell surface receptor, called PD-1, have revolutionized cancer treatment. However, more than half of cancer patients don’t respond well to this immunotherapy,” explained Madhu Malinee, a doctoral student at Kyoto Univeristy and the study’s first author.

“One of the major reasons for this unresponsiveness is that these patients have an insufficient number of T cells that also become exhausted because they don’t have enough active energy-providing mitochondria,” added Ganesh Namasivayam Pandian, PhD, associate professor at Kyoto University’s Institute of Integrated Cell Material Sciences (iCeMS).

The researchers sought to increase the mitochondria in T cells to improve cancer patient response to PD-1 blockade monotherapy. However, a challenge to achieving this has been finding a way to selectively target PGC-1.

To overcome this challenge, the researchers used a compound, called pyrrole-imidazole polyamide (PIP), that can be programmed to target a specific DNA sequence. They assembled it as a molecular code, called EnPGC-1, that can activate PGC-1.

The researchers observed that EnPGC-1 activated the mitochondria of mouse T cells in the laboratory. The tumor-bearing mice were then given a combination of EnPGC-1 with PD-1 blockade immunotherapy and they found that the strategy enhanced anti-tumor immunity in the mice and improved their survival.

“Further improvements are needed before the approach can be tested for clinical use,” added Pandian. For example, the team aims to find ways to deliver EnPGC-1 specifically to T cells to reduce its off-target effects.