Frederick National Laboratory researchers identified a vitamin A derivative (retinoid) that when combined with a standard immunotherapy will shrink otherwise checkpoint-resistant lung tumors in mice, a potential step toward human clinical trials to improve lung cancer treatment.
The research, described in Scientific Reports, focused on all-trans-retinoic acid (ATRA), a vitamin A metabolite that regulates growth and differentiation of malignant cells through three subtypes of retinoic acid receptors (RARs) α, β and γ. It can stimulate cellular growth or shut it down, depending on the cell context. In this work, these scientists were looking for a way to capitalize on ATRA's power to stop growth, but without activating its growth-promoting ability.
Experiments were conducted in laboratory mice with lung cancers. First the scientists tried a RARα antagonist (IRX6696) that would specifically impede retinoic acid receptor α activity and combined it with an immunotherapy, anti-PD-L1, a widely used checkpoint blockade. This approach was unsuccessful.
Next, they tried a RARγ agonist (IRX4647) to specifically stimulate retinoic acid receptor γ, combined with the immunotherapy. This combined regimen successfully antagonized the growth of mouse lung cancer tumors and did so against cancers that previously resisted treatment with the immunotherapy. This agent was provided by Io Therapeutics, Inc.
Anti-PD-L1, an immune checkpoint blockade, proved a decisive breakthrough against cancers, but not in all cases. The treatment directs the immune system to kill cancer cells by undoing cancer's ability to hide from an immune system attack. The average response rate is 20 percent to 50 percent. There is a great interest in finding ways to make the therapy more widely effective.
"Augmenting the clinical efficacy of immune checkpoint blockade is currently an unmet medical need," the scientists reported. Yet, "It remains to be discerned if these promising preclinical findings will translate into the cancer clinic."
Before that can proceed, toxicology studies are needed to determine safe tolerance levels for IRX4647 in humans. Also, pharmacokinetic and pharmacodynamic studies in humans are needed to determine the optimal drug dosing regimen in patients.
The research was conducted at Frederick National Laboratory in the laboratory of the Molecular Pharmacology Program, supervised by Xi (Hill) Liu, Ph.D., senior principal scientist, and Ethan Dmitrovsky, M.D., president of Leidos Biomedical Research and director of the Frederick National Laboratory for Cancer Research.