Over the past few years the entire landscape of cancer therapy has been transformed by immunotherapy with checkpoint inhibitors (i.e., anti-CTLA-4 and anti-PD-1). These agents have had their most remarkable impact on the treatment of melanoma. Understanding the mechanisms of response (tumor shrinkage) and resistance (tumor growth) to checkpoint inhibitors will provide us an ability to select patients with the greatest likelihood of benefiting from therapy, avoid toxicity in those without benefit, direct improvements at melanoma patients unlikely to benefit from checkpoint inhibitor (anti-PD-1) alone, and better select patients with less responsive cancers for therapy. With numerous collaborators, we are finding that when tumors express the MHC-class II then they are more likely to respond to the checkpoint inhibitor, anti-PD-1; by using a widely available limited panel of cancer genes, we have developed a method to estimate the overall number of genetic mutations in a tumor and through this estimated mutational load identify patients with greatest likelihood of responding to anti-PD-1 therapy. We are now planning a clinical trial to select cancer (all solid tumors) patients for anti-PD-1 therapy based on the “high” number of mutations. Finally, we have performed studies with melanomas directly obtained from patients to understand basic, fundamental changes within the melanoma exposed to targeted drugs and immune checkpoint inhibitors. This has been performed with experiments that define global changes at the level of the DNA (genomics), mRNA (transcriptome), and the non-genomic (epigenomic) factors that regulate the expression of genes and their products, proteins.
|Effective start/end date||5/1/16 → 12/31/19|
- American Cancer Society (Grant #RP-14-246-06-COUN)