Summary authored by Julia Blanter, MD

Drug-based Immunotherapy

Julia Blanter, MD

As part of our drug development lecture series, Dr. Nilofer Azad presented on drug-based immunotherapy. Dr. Azad is the co-director of cancer genetics and epigenetics at Johns Hopkins University School of Medicine. She directs the developmental therapeutics clinical trials program at the Johns Hopkins Sidney Kimmel Cancer Center. Her disease focus is primarily in gastro-intestinal cancers. Her session on early phase clinical trials focused on immunotherapy combination approaches. Interestingly, a majority of drug development is immunotherapy focused. She discussed the current redundancy in the market with a continued surge of new immune checkpoint inhibitors but a serious lack of other approaches. This is especially relevant for diseases classified as “cold” tumors that have not shown response to immune checkpoint inhibition. Many of these diseases are the top causes of cancer mortality; for example, microsatellite stable (MSS) colon cancer, hormone positive breast cancer, and prostate cancer. 

Dr. Azad described the complicated nature of tumors that don’t respond to immunotherapy. Tumors have been classified as either being “cold “or “hot”. Hot” tumors are the immune-inflamed tumors that characteristically respond well to immunotherapy. Non-small cell lung cancer, melanoma and renal cell carcinoma are some examples of classically “hot” tumors. On the other hand, there is an absence of T cells and antigen presenting cells in “cold” tumors. Examples of tumors that have been characterized as “cold” neoplasms include hormone positive breast cancer, castration sensitive prostate cancer and pancreatic ductal adenocarcinoma. Many previous studies have examined how to make a “cold” tumor “hot.” In other words, these studies have focused on how to reverse the immunosuppressive microenvironment of cold tumors to attract a more immune-inflamed environment. However, it has become increasing clear that their architecture goes far beyond being classified as “cold” vs. “hot.” In addition, there exists the immune-excluded phenotype that has a walled off tumor microenvironment. Dr. Azad also went on to describe a myeloid and mesenchymal immune phenotype that would likely respond to different immunotherapies. 

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.