The concept of immunotherapy or boosting the body’s immune system to target tumors was first practically applied in the early 20th century. An American physician named William Coley treated cancer patients by administering a lethal cocktail of bacteria. Interestingly, after a severe fever, the tumor shrank in size. In this case, the lethal bacteria elicited a strong immune response to fight the microbes injected. The tumor was recognized from the bacterial response. Since then, scientists and researchers have worked to more accurately target cancer by boosting specific immune cell populations.
The immune system is comprised of different immune cells that provide initial and long-term immunity. Coley’s bacteria toxin was effective, because the body recognized the bacteria as foreign and elicited strong immunity against it. Normally, specialized immune cells known as T cells can destroy tumors, but cancer can evade detection by the immune system. They can do this a variety of ways including, deactivating T cell activity. Current immunotherapies are employed to overcome different tumor suppressing mechanisms and reactivate the immune response. A common immunotherapy that has revolutionized the way physicians treat patients include checkpoint inhibitors (ICIs), which block receptors on tumors or T cells that lead to T cell activation. However, ICIs have limited efficacy in some tumors due to the enzyme, immunomodulatory enzyme indoleamine 2,3 dioxygenase 1 (IDO1), that metabolically shifts the way tumors produce energy and induce immune suppression. This enzyme is present in healthy cells, but upregulated in tumors which contributes to tumor progression. Scientists have recently discovered that IDO1 inhibition with checkpoint inhibitors can improve therapeutic efficacy.
A recent study in Nature Chemistry, by Dr. Herbert Waldmann and others, demonstrated that IDO1 is a critical biomarker necessary to inhibit for therapeutic benefit in cancer. Waldmann is Full Professor and heads the Department of Chemical Biology at the Max Planck Institute of Molecular Physiology. His work focuses on biochemical approaches to treat disease, particularly cancer. Waldmann is world renowned for his work and has been awarded the Emil-Fischer Medal by the German Chemical Society, which is one of the highest distinctions in the field of organic chemistry.
The team used various laboratory techniques and modeling systems to understand the benefit of targeting IDO1. In the study, researchers developed a novel system to quantify IDO1 from cells to measure IDO1 inhibitor potency. By screening over 150,000 compounds, Waldmann and his group were able to identify a way to completely block IDO1 function compared to the inhibitor in a current late-stage Phase III clinical trial. Researchers began looking for alternative therapies because the clinical trial was not improving patient outcomes. While it was unclear why the clinical trial was unsuccessful, researchers suspect that it was due to the fact that incomplete IDO1 inhibition paradoxically allows for an increase in IDO1 protein. This increased quantity of IDO1 provides further tumor protection, limiting efficacy. Therefore, scientists have identified a new class of drugs that degrade instead of inhibiting IDO1. The drug specifically induces a structure change that tags the enzyme with a molecule, known as ubiquitin. The tagged enzyme is then degraded by other intracellular enzymes. Consequently, this process completely gets rid of IDO1 function and sensitizes tumors toward immunotherapy.
The unique mechanism of this new IDO1 degrader provides insight into novel therapeutic approaches in cancer. As a result, this degrader can effectively resolve the current problem with IDO1 inhibitors and be paired with ICIs to improve clinical outcomes. Overall, this work suggests a novel drug alternative that can prolong patient survival and enhance quality of life.
Study, Nature Chemistry, Herbert Waldmann, Max Planck Institute of Molecular Physiology
