A novel predictive tool developed by researchers at Dana-Farber Cancer Institute may help guide immunotherapy choices for patients with advanced melanoma. The tool uses a machine learning model based on a tumor's genomic heterogeneity and ploidy to predict resistance to anti-PD-1 therapy, potentially allowing clinicians to better select between single-agent and combination immunotherapy approaches. This research, published in Science Advances, could lead to more personalized and effective treatment strategies for melanoma patients.
Identifying Resistance to Anti-PD-1 Therapy
Immune checkpoint inhibitors, particularly anti-PD-1 therapies, have revolutionized the treatment of advanced melanoma. However, while some patients experience significant benefits from single-agent immunotherapy, others do not respond or eventually develop resistance. Combination immunotherapy, involving two immune checkpoint inhibitors, can yield higher response rates but also carries a greater risk of toxicity. Currently, there are limited biomarkers to help physicians determine which patients are most likely to benefit from single-agent therapy versus combination therapy.
Giuseppe Tarantino, PhD, and David Liu, MD, MPH, along with their team, built upon previous research indicating that genomic heterogeneity (the tumor's propensity to develop new mutations) and low genomic ploidy (a measure of the number of chromosomes in the cells) are associated with resistance to anti-PD-1 therapy. They developed a machine learning model that integrates these factors to predict resistance.
Validation and Potential Clinical Impact
The research team refined and validated the model across four cohorts, including data from two clinical trials. The interpretable machine-learning algorithm employs a simple decision tree to predict which patients are likely to resist immune checkpoint blockade with anti-PD-1 therapy. In a small group of thirteen patients, 43% predicted to be resistant to single-agent therapy responded to combination therapy, suggesting the tool's potential to guide treatment decisions.
"Immune checkpoint inhibitors have dramatically improved outcomes for patients with advanced melanoma," the researchers noted. "This study describes a predictive tool that can be used to choose between these two options by predicting which patients are likely to fare poorly with single-agent therapy and therefore might benefit from combination therapy."
Future Directions
Future research will focus on prospective studies using existing clinical sequencing tests to determine whether the tool can effectively guide therapy choices and improve outcomes for melanoma patients. The goal is to integrate this predictive tool into clinical practice, enabling more informed and personalized treatment decisions for patients with advanced melanoma.
