Immunotherapy before surgery for glioblastoma shows promise

Glioblastoma is the most common, aggressive and deadly form of brain cancer. Median overall survival for primary glioblastoma is 14.6 months with the standard treatments of surgery, radiation therapy and the chemotherapy temozolomide, and falls to 5.5 – 11 months for recurrent glioblastoma.

Tumor heterogeneity and the blood-brain barrier make it difficult to treat glioblastoma. Immunotherapies such as immune checkpoint inhibitors, which have shown great promise in activating the immune system to attack other cancers like leukemia and melanoma, have only recently been investigated for glioblastoma patients.

But results from a recent study conducted by researchers at the University of California at Los Angeles and six other participating institutions, including MD Anderson Cancer Center, are offering encouragement for the use of immunotherapy in helping these patients.

Published this week in Nature Medicine, the study shows that patients who were given the immune checkpoint inhibitor pembrolizumab before glioblastoma surgery lived on average twice as long as those given the PD-1 inhibitor after surgery. It’s the first study to show survival benefit for patients with glioblastoma who received neoadjuvant pembrolizumab, which blocks programmed cell death protein 1, also known as PD-1. PD-1 helps regulate the immune system’s response to avoid autoimmunity but also can prevent the immune system from targeting cancer cells.

The randomized, open-label study included 35 patients with recurrent, surgically resectable glioblastoma: 16 patients received two doses of pembrolizumab before surgery and continued to receive pembrolizumab after surgery (neoadjuvant group), and 19 patients received pembrolizumab only after surgery (adjuvant group).

Hopeful results could change doctors' approach

“This study could change the way we treat patients with recurrent glioblastoma,” says John de Groot, M.D., an author of the study and interim chair of Neuro-Oncology at MD Anderson. “One of the surprising aspects of this study was that most patients in the neoadjuvant group benefited, so it is unlikely that these results were due to chance. Our findings need to be validated, but it appears that neoadjuvant pembrolizumab could work for a broad group of patients.”

Pembrolizumab has shown survival benefit in several other cancer types, but primarily as an adjuvant monotherapy. Recent studies in metastatic breast cancer, resectable lung cancer and melanoma have shown that neoadjuvant checkpoint inhibitors can increase antitumor immune responses compared to the same drugs used in an adjuvant setting. In this study, timing of immune checkpoint inhibition also appears to be crucial to the efficacy of the drug for glioblastoma patients.

Longer survival, better outcomes

As of the analysis cutoff date (July 2, 2018), patients in the neoadjuvant group had a median overall survival of 417 days (13.7 months), which was significantly longer than the adjuvant group (228 days [7.5 months]). Patients in the neoadjuvant group did not experience new toxicities, and many of the adverse events that were reported during the study are frequently experienced by patients with central nervous system tumors and/or those who have received corticosteroids.

“It’s exciting because up to now, immunotherapies looked like they were going down the road for everything else — ‘Oh, they work in peripheral tumors, but not in the brain,’” Frederick Lang, M.D., chair of Neurosurgery, said in an interview with STAT about the study. Lang conducts immunotherapy research but wasn’t involved in this trial. “This study really infuses hope back into the field, that these checkpoint inhibitors may be effective if we use them in the correct way.”

Analysis of tumor samples provides insights

The study also used T cell receptor sequencing, gene expression profiling, quantitative multiplex immunofluorescence, and mass cytometry to analyze tumor tissue samples from the patients to determine pembrolizumab’s mechanisms of action. Their findings suggest that neoadjuvant pembrolizumab initiates a local and systemic T cell response. Pembrolizumab systemically activates tumor-infiltrating lymphocytes, which increases transcription of genes related to interferon gamma and inhibits the transcription of tumor cell-cycle genes (thus inhibiting tumor cell proliferation). Pre-surgical checkpoint inhibition increases tumor-specific T cells; if the tumor has already been resected, the immune system produces fewer tumor-specific T cells, and residual tumor cells proliferate more rapidly.

The study’s findings also suggest that T cell receptor diversity may help sustain the immune system’s ability to attack tumor cells, so the researchers plan to combine neoadjuvant pembrolizumab with a CTLA-4 checkpoint inhibitor, which has been shown to promote the diversity of T cell receptors in patients with melanoma. CTLA-4 inhibition has not been investigated in the neoadjuvant setting, but as with pembrolizumab, timing may prove important for CTLA-4’s efficacy in patients with recurrent glioblastoma.