Summary authored by Julia Blanter, MD

Drug-based Immunotherapy

Dr. Azad touched on histone de-acetylation inhibition as a method to change the post-translational modification of histone proteins and create a more open conformation to allow for gene transcription. This process modulates myeloid cell populations and may sensitize immune-resistant pancreatic ductal adenocarcinoma to immune checkpoint inhibitor therapy. She discussed trials of histone de-acetylation inhibition in combination with immune checkpoint inhibition reducing immunosuppressive macrophages in the tumor microenvironment of pancreatic ductal adenocarcinoma. She further discussed her work with MEK inhibition in combination with immune checkpoint inhibition in cholangiocarcinoma. Lastly, she discussed her work looking at the PIK3CA activation conferring resistance to immune checkpoint blockade and exploring PIK3CA inhibition in combination with immune checkpoint inhibitors.

There are many novel, exciting therapies to employ in combination with immune checkpoint inhibition that may have promising effects in those populations that have not classically responded to immunotherapy. However, it will be important to approach these studies differently from a classic phase 1a trial design (such as 3+3). This is especially important as our primary goal shifts from finding the maximally tolerated dose to finding safe and effective combination therapies that work on tumors classically resistant to immunotherapy.