Battles on multiple fronts: The power of combination immunotherapy in cancer treatments

The human immune system is built on a foundation of complex networks. Together, many different types of immune cells and organs do everything from staving off infection to killing cancerous tumors. Inspired by the immune system’s versatility, scientists have been exploring its uses in cancer treatments by directly targeting some of these cells, an approach called immunotherapy. 

A promising method of treating cancer is combination therapy, which can be done in multiple ways. A study led by Kevin Wang at the University of Pennsylvania experimented with targeting two common checkpoint inhibitors: PD-1 and CTLA-4. Checkpoint inhibitors keep the immune response in check, allowing “fighter” white blood cells called T cells to kill tumors. Wang and his team used this combination therapy on a model for advanced melanoma. The previous understanding of checkpoint inhibitors was that they released T cells into the body, which would eventually wear out and be unable to continue fighting cancerous cells. In order to keep up the battle, the immune system would have to strengthen the T cells. The results of this study, however, showed that the combination therapy generates a clonal response. Each dose of the treatment brought on a new wave of T cells rather than strengthening the existing ones. Therefore, immune checkpoints would remain effective until the supply of T cells ran out, not just when the cells became exhausted. 

Wang’s lab also piloted their Cyclone algorithm, which can track the movements of individual T cells as well as the magnitude of the immune response they generate. With new understandings of the behavior of immune cells and technology like Cyclone, researchers can continue to discover how targeting multiple checkpoints can increase the versatility of their treatments. 

The field of immunotherapy has rapidly expanded due to technological advances and innovative research. However, treatments are hardly one size fits all, and their efficacy can heavily depend on where or how the medicine is taken. Another type of combination immunotherapy involves integrating administration sites and medication types. Topical administration is applied locally, typically by creams, lotions, or gels. Systemic administration refers to medication that enters the bloodstream, such as painkillers taken orally. 

Maria Sibilia, a researcher from the Medical University of Vienna, led a study that combined systemic and topical administrations to treat models of melanoma and breast cancer. These particular cancer types were chosen because they are accessible to local therapy administration and they often form distant metastases, or growths in areas beyond the original tumor. They found that using two different therapies, which were administered in different ways, not only killed cancerous cells at the tumor sites but also fought metastases. This is because it activated the adaptive, or acquired, immune system. While the innate immune system provides standard protection against infection and foreign invaders, the adaptive immune system is built over time and is able to remember diseases it’s exposed to. By activating this division of the immune system,

the combination medication was able to address metastases across the body in addition to the tumor growth at the original site.

Cancer treatment has come a long way thanks to combination immunotherapies. Several checkpoint inhibitor treatments are already widely used in patients, and others are being actively researched.

By targeting checkpoint inhibitors or utilizing multiple administration routes, these therapies can have increased efficacy and lead to better outcomes for patients.