Immunotherapy has reshaped the cancer treatment landscape. This type of treatment boosts the immune system to fight cancer. However, for people with advanced brain cancer, immunotherapy options remain slim. Here, our Curious Dr. George asks Cancer Commons Scientist Matt Warner, PhD, about the challenges and future potential of immunotherapy for brain cancer.
Curious Dr. George: An accomplished molecular oncologist, you have now helped many brain cancer patients consider their options, both on your own and as part of virtual tumor boards. Immunotherapy has successfully revolutionized the treatment of many potentially lethal cancers. Why has the use of immunotherapy for brain malignancies seemed to lag?
Matt Warner, PhD: There are several reasons why cancers of the central nervous system (CNS) have been more challenging than other cancers to treat with immunotherapies. Despite recent studies demonstrating that the CNS is not as “immune privileged” as we once believed, it is still clear that 1) the unique anatomy of the brain and spinal cord, 2) the role of the blood-brain barrier at controlling which substances and immune cell subtypes can access the CNS, and 3) the limited presence of the lymphatic system within the CNS all decrease the ability of the immune system to patrol and attack cancers within the CNS versus other organs of the body.
Furthermore, CNS cancers often display fewer mutations in comparison to other cancers and therefore lack the immunogenicity to help the immune system identify and distinguish the cancer from the healthy neuronal tissue.
Lastly, as with all other cancers, you then have to compete with the immunosuppressive tumor microenvironment and the knowledge that chronic and excessive neuroinflammation as a result of hyperactivation of the immune system could also be detrimental to a patient. This presents concerns from a quality-of-life standpoint due to the impact of inflammation and swelling on the function of healthy neuronal tissue. It also poses disease management concerns because the immune system’s response to CNS cancer may also impact the survival, proliferation and invasiveness of gliomas.
CNS cancers therefore present some unique challenges for the immunotherapy-based treatments we currently have available in the clinic, highlighting why the clinical development of immunotherapies for these cancers has been less successful.
Despite these setbacks, I still believe immunotherapies will play a significant role in treating CNS cancers in the future. However, in order to be successful, this approach will most likely require novel combinations of immunotherapy-based treatments (for example, immune checkpoint inhibitors, dendritic cell and peptide-based anti-cancer vaccines, oncolytic viral therapies, and cellular therapy) with radiation, chemotherapies, targeted therapies, and/or Optune. Such combinations will no doubt help us move beyond the prior failings of immunotherapies being investigated as single agents, which lack the necessary activity to single-handedly enhance the immune system and treat cancers within the CNS.
Recent research findings provide some hope in this regard. For example, interim analyses from ongoing clinical studies and retrospective analyses from closed trials that investigated immune checkpoint inhibitors in glioma patients demonstrate that these drugs may need to be used around the time that patients are receiving their surgery, radiation therapy, or Optune treatment, and they may need to be targeted to patients with unique tumor mutational profiles. Additionally, more trials are now exploring combinations of immunotherapies and pharmacological agents to (hopefully) modulate the tumor microenvironment and make it more amenable to immunotherapy-based treatments.
Given how little we still understand about the brain and the activity of the immune system within the CNS, I am confident that we will one day celebrate the successes of immunotherapies in the treatment of CNS cancer patients.
Matt can be reached at firstname.lastname@example.org.