Determining how Brain Tumors Suppress Immune Responses may Accelerate Immunotherapy Advances

Lay Summary

Determining how brain tumors suppress immune responses may accelerate immunotherapy advances

This study aims to understand the molecular genetics of deadly brain glioblastomas (GBMs) and their interactions with the immune system, which may help improve the effectiveness of immunotherapies in this disease. Breakthroughs are critically needed since no significant progress has been made in treating GBMs in decades, and patients rarely survive more than 20 months.

GBMs arise from non-neuronal brain cells, called glia. These cells provide supportive functions to brain cells. They also generate immune responses which, in the healthy brain, are kept in check by brain cells. GBM treatment has for decades focused on testing various types of drugs in combination with radiation after surgical removal of tumor tissue, but with overall dismal results. Progress in developing “immunotherapies” to strengthen immune responses in other cancers have spurred interest in immunotherapy approaches to treating GBM. The approach is not without its challenges. While brain invaders such as viruses create signals, or “antigens,” which immune cells can identify as foreign and attack, GBMs are derived from the patient’s own glial cells. So immune cells recognize the antigens are “self’ and do not attack. This process, which evolved to protect the body’s own healthy tissues from “autoimmune” attacks, results in the immune cells’ “tolerance” to the brain tumor.

Nonetheless, the glial cells’ cancerous mutations that promote their malignancy do produce a molecular signature that distinguishes them from their normal counterparts. Immune cells need to recognize these tumor-specific antigens before the cells organize into a solid tumor. One approach is to try to develop therapeutic vaccines that teach immune cells to recognize and attack the new antigens, much like preventive vaccines prepare immune cells to detect and attack viruses. That approach has proven difficult so far.

Another approach is called “checkpoint” inhibitor therapy. This type of therapy is designed to keep the malignant cells from co-opting the signaling that normally protects tissues against a mistaken autoimmune attack. Two signals are needed before immune T cells attack. The first signal comes from the GBM cell surface. This signal turns on the immune T cell. Before attacking the GBM cell, though, immune T cells require a second signal. This signal comes from a “co-stimulatory” molecule. This second signal gets blocked by “checkpoint” molecules. Checkpoint molecules are extremely complicated. Each checkpoint molecule has a distinct function, specific effects on local or systemic immune responses, and signals alone or in combination with others.

Inhibiting these checkpoint molecules, therefore, is complicated, but feasible since GBM cells re-program immune cells to suppress their actions locally within the tumor microenvironment and systemically (circulating remotely in the bloodstream). Evidence suggests that two checkpoint molecules maintain immunosuppression in GBM patients: the CTLA-4 molecule blocks immune T cell activation in lymph nodes, and the Programmed Death (PD-1) molecule inhibits immune activation in circulating blood. So far experimental checkpoint inhibition therapy has been disappointing, but this immunotherapy approach has yet to be initiated prior to radiation, chemotherapy, and corticosteroids – all treatments that subsequently suppress the immune system. The investigators suspect that if checkpoint inhibition therapy occurs first, in a “window of opportunity” after initial surgical resection and prior to such other immunosuppressing therapies, outcomes might be better.

The investigators hypothesize that identifying subtypes of patients with GBM based on the immune composition of their tumor “microenvironment” will provide predictors of response to immunotherapy treatment using the antibody ipilimumab to inhibit lymph node CTLA-4 signaling, and the antibody nivolumab to inhibit peripheral PD-1 signaling.

The investigators will first study brain-immune interactions at the molecular genetic level to reveal how GBM cell genes adapt to the tumor environment in the brain. They will identify genes’ structure and function by studying the RNA that carries out their instructions. In essence, they will create a “bar code” that they can use to track relative changes in tumor cells, local immune cells, and immune cells in the periphery. This will provide a broad characterization of the tumor microenvironment across large numbers of GBM samples. They will then identify genetic and immunologic subtypes to characterize how tumor cells change their molecular composition and how changes occur in the local and peripheral checkpoints that block immune activation, and in the immune cells. Finally, they will determine subtype responses among 45 newly-diagnosed GBM patients participating in their clinical trial of upfront immunotherapy treatment with the two antibody checkpoint inhibitors, nivolumab and ipilimumab, prior to receiving any chemotherapy or radiation. They will characterize longitudinal changes in each subgroup of patients, including’ brain tumor molecular profile, local tumor microenvironment, and systemic immune responses that occur after checkpoint inhibitor immunotherapy. The lead neurosurgeon, additionally trained in computational biology, anticipates that this systems biology approach will lead to understanding brain immune therapy responses to further refine and improve future treatment strategies.