Checkpoint blockade immunotherapies have benefited many cancer patients, but are still only effective in roughly 30% of cancers. In many cases, normal cells provide support to cancer cells and render these therapies ineffective. As a result, doctors are now turning to strategies that address the tumor microenvironment (TME), the complex network of immune cells, stromal cells, and extracellular matrix proteins with which cancer cells interact.
Leading off the morning, Dr. Elizabeth Jaffee, a member of CRI’s Scientific Advisory Council and leadership committee of the CVC Trials Network housed under CRI’s Clinical Accelerator, proposed ideas to better treat pancreatic cancer, by turning it into an immunological disease by altering the TME. Unlike cancers, such as melanoma, that respond to checkpoint immunotherapy, pancreatic cancer is not very immunogenic, or visible to the immune system as dangerous. T cells, which carry out anti-tumor immune responses, are rarely found. Instead, the TME is infiltrated with suppressive immune cells such as monocytes, macrophages, and myeloid-derived suppressor cells that support cancer and dampen anti-tumor immunity.
This makes pancreatic cancer a good model for this TME-targeting approach. If we can figure out how to convert a pro-cancer TME to an anti-cancer TME in particularly non-immunogenic cancers like pancreatic cancer, similar strategies could then be tried against other non-immunogenic cancers.
One strategy involves targeting dendritic cells (DCs) that can mediate anti-tumor responses, but typically remain stuck in an immature, and hence ineffective, state. GVAX, a vaccine created by CRI Scientific Advisory Council associate director Glenn Dranoff, M.D., uses genetically modified cancer cells designed to produce a molecule called GM-CSF that can recruit immature DCs to tumors and promote their maturation. Mature DCs can then recruit and activate T cells and allow them to carry out anti-cancer activity.
For pancreatic cancer patients receiving therapy for the first time, outcomes could be improved by first debulking their tumors with chemotherapy, and then treating them with GVAX and a checkpoint inhibitor such as the anti-CTLA-4 antibody ipilimumab or the anti-PD-1 antibodies pembrolizumab or nivolumab, to promote high T cell activity.
To complement all of these approaches, Jaffee noted, we must also develop better biomarkers to guide treatment decisions as well as gauge patient responses to determine if therapies are working or not. This is especially important in the case of pancreatic cancer, which takes longer to show responses according to conventional criteria related to tumor volume.
Coming up later today: combination immunotherapies and overcoming cancer’s ability to resist treatment.