Article In Brief
Researchers reported that an immunotherapy administered prior to surgery for glioblastoma resulted in longer survival. Several independent experts said the results, however groundbreaking, will need to be replicated in larger trials.
Administering pembrolizumab, a programmed cell death protein 1 (PD-1) monoclonal antibody, prior to surgical resection for recurrent glioblastoma multiforme (GBM) appears to result in better survival than adjuvant therapy after surgery, according to a report published online February 11 in Nature Medicine.
[Pembrolizumab is one of several agents known as checkpoint inhibitors, which work by blocking the receptors that cancer cells use to send signals to T cells. When the signal is blocked, T cells may be better able to distinguish a cancer cell from a healthy cell and launch an attack. Checkpoint inhibitors are designed to block either PD-1 or programmed cell-death ligand (PD-L1), exposing the cancer cell for attack.]
Study authors and experts who reviewed the report for Neurology Today said immunotherapy prior to surgery, when a significant tumor mass exists, appears to promote cell death processes in the tumor microenvironment as well as systemic anti-tumor immune response not seen in adjuvant therapy after surgery.
“Anti-PD-1 blockade in the neoadjuvant setting in patients with recurrent, resectable glioblastoma appears to provide a survival benefit,” study co-author Aaron Y. Mochizuki, MD, a pediatric hematology/oncology fellow at David Geffen School of Medicine at University of California, Los Angeles (UCLA), told Neurology Today.
“This is likely driven by the systemic modulation of the immune compartment, wherein tumor-specific T cell clones after checkpoint release can become activated and expand in response to the large antigenic burden present with the tumor still in place. After surgery, this broader repertoire of tumor-specific T cells can continue to eliminate residual tumor cells.”
Dr. Mochizuki explained that T cells in and around the tumor are functionally suppressed by the tumor cells' use of the PD-1 axis, which typically is a mechanism that prevents the immune system from attacking the body's own cells.
“By administering PD-1 blockade, the T cells wake up and recognize the tumor as foreign,” he told Neurology Today. “When T cells become activated, they release interferon gamma, which recruits other immune cells to the area and enables tumor-specific T cells to proliferate. We think that checkpoint release prior to surgery is important because you have more tumor cells available that T cells can recognize.”
“Surgery is also essential,” he continued, “but if you take the tumor out before waking the T cells up, there's not enough cancerous cells left over after for the T cells to recognize and so their typical immune signaling through interferon gamma is not as robust; subsequently fewer other immune cells are recruited, and the immune system's ability to respond to the tumor is not as strong as it could be.”
The lead study author, Timothy F. Cloughesy, MD, director of the neuro-oncology at the Geffen School of Medicine at UCLA, other UCLA scientists, and investigators included investigators at the Ivy Foundation Early Phase Clinical Trials Consortium. They enrolled and randomized 35 patients—16 to neoadjuvant pembrolizumab and 19 to adjuvant therapy only—between October 2016 and September 2017 at seven institutions. There were no statistically significant differences in age, sex, pre- or post-surgery tumor volume, steroid administration at registration, or other prognostic factors. The extent of resection or the fraction of patients who received a gross total resection was not different between groups.
As of the analysis cutoff date, there have been nine deaths in the neoadjuvant arm and 12 in the adjuvant-only arm. The neoadjuvant arm demonstrated a statistically significant increase in overall survival: Patients in the adjuvant-only group had a median overall survival of 228 days (7.5 months), whereas those in the neoadjuvant arm had a median overall survival of 417 days (13.9 months).
“The study is highly provocative, preliminary, exciting, but does not represent a new standard of care, only an important new approach. It needs to be confirmed in future, prospective, randomized studies to be the new gold standard.”'
—DR. STEVEN BREM
Importantly, Dr. Mochizuki and colleagues were able to demonstrate that the survival benefit was associated with intracellular changes in anti-tumor immunological response and tumor replication processes.
For instance, they analyzed transcriptional changes within patient tumors and found that neoadjuvant PD-1 blockade induces distinct tumoral gene expression changes: Interferon- and T cell–pathway induction was observed in nine of 14 tumors in the neoadjuvant group and five of 15 in the adjuvant-only group. Additionally, three out of 14 tumors in the neoadjuvant group demonstrated positive enrichment of cell cycle/cancer proliferation signatures, whereas this occurred in 11 of 15 tumors in the adjuvant group.
They also found that neoadjuvant PD-1 antibody blockade is associated with increased T-cell density: Seven patients who had neoadjuvant therapy compared with just three who had adjuvant therapy exhibited high CD8 T-cell infiltration, suggesting that neoadjuvant treatment is associated with induction of PD-L1 expression.
Dr. Mochizuki said anti-PD-1 blockade in the neoadjuvant setting is just starting to gain traction. “The risks of immunotherapy are relatively well-known,” he said. “Immune-related effects, such as hepatitis, colitis, thyroiditis, are the most concerning, though we can't say for certain at this point whether neoadjuvant administration of PD-1 blockade increases the risk of these adverse events.”
Dr. Mochizuki added: “There is certainly still a great deal to learn about the use of neoadjuvant PD-1 blockade in patients with recurrent glioblastoma. As such, we're expanding the trial to include more patients on the neoadjuvant arm. Our findings will need to be replicated in larger studies before this becomes standard of care....Given the dismal prognosis associated with recurrent glioblastoma and the limited number of new treatments over the past several years, we believe that this represents a promising new approach to the disease.”
Experts who reviewed the paper for Neurology Today agreed the report is groundbreaking, offering a potential life-extending therapy for an aggressive and fatal form of cancer.
“The report has shaken up the field a bit,” said Sylvia Kurz, MD, PhD, assistant professor in the departments of medicine and neurology at NYU Langone's Perlmutter Cancer Center. “GBM is an aggressive, fatal brain tumor, for which there is currently no cure. The survival with radiation and chemotherapy is dismal—one-and-a-half years to two years.”
“Based on the success of immunotherapies in other fields of oncology there has been a lot of hope around the use of checkpoint inhibitors [like PD-1] and evidence that they have rendered some cancers stable and controllable,” Dr. Kurz said. “Unfortunately, enthusiasm about immunotherapies for brain cancers has been dampened in the field of neuro-oncology based on studies in recurrent GBM, where these therapies have not had the same success.”
What is novel in the new study and possibly explanatory is the use immunotherapy prior to surgery, when there is enough tumor mass to “educate” the intra-cellular immunological response. “The strength of the study [by Dr. Cloughesy and colleagues] is their detailed molecular analysis of the cellular changes in the tumor microenvironment and in the blood stream,” said Dr. Kurz. “Based on this study, we may have to revise our thinking about how we use these therapies and consider treating patients before surgery when there is more tumor present.”
Steven Brem, MD, co-director of the Penn Brain Tumor Center at the Hospital of the University of the Pennsylvania, said the study by Dr. Cloughesy and colleagues is “an exciting and important paper that supports the current work at Penn and other centers to harness the immune system to effectively combat glioblastoma.”
The neoadjuvant approach to immunotherapy and brain cancer may provide a unique clinical development path while also providing a therapeutic window to study the immunobiology of malignant brain tumors, Dr. Brem said. He noted that work at Penn has showed that T-cell therapy can be biologically effective when targeted to human glioblastoma as evidenced by T-cell trafficking into the tumor, immuno-editing of the target antigen, and clonal expansion of the T-cells systemically.
But he said the barriers to realizing the full potential of T-cell therapy include the immunosuppressive microenvironment and glioma cell heterogeneity. In order to overcome the immunosuppressive environment, one approach is to use immune checkpoint inhibitors, such as PD-1 inhibitors like pembrolizumab. “The overall goal is to convert an immune-excluded or ‘cold’ tumor such as glioblastoma into a ‘hot’ immune-active tumor.”
Dr. Brem said the Nature Medicine study is preliminary but is compelling. He envisions that it will also influence clinical trial design and spur more studies of immunotherapeutic approaches in human glioblastoma that can prolong survival in a relatively nontoxic manner, complementing the current approaches approved by the US Food and Drug Administration.
“Neoadjuvant pembrolizumab confers significant improvement in overall and progression-free survival in patients with recurrent glioblastoma,” he said. “Significantly, neoadjuvant PD-1 blockade induced relevant immune cell activation within the tumor microenvironment that subsequently repressed the cell-cycle-related transcriptional activity of tumor cells.”
“Based on this study, we may have to revise our thinking about how we use these therapies and consider treating patients before surgery when there is more tumor present.”
—DR. SYLVIA KURZ
He added that risks associated with neoadjuvant therapy are few. No patients in the neoadjuvant group had surgery delayed because of adverse events before tumor resection, he said. “Known risks of using pembrolizumab include pneumonitis, but overall the drug is well-tolerated.”
Exciting as the findings are, replication in prospective studies is necessary before neoadjuvant immunotherapy can be considered a standard of care. “We have to get more data in larger prospective clinical trials,” Dr. Kurz told Neurology Today. “This study was performed with patients with recurrent GBM. An important question to be explored is whether it can be applied to newly diagnosed GBM. That's a challenge because ideally you would want to make the diagnosis before committing the patient to an experimental therapy. So there's a lot of work yet to be done.”
“I think we should be careful and not overshoot our optimism,” she said.
Dr. Brem agreed. “The study is highly provocative, preliminary, exciting, but does not represent a new standard of care, only an important new approach,” he said. “It needs to be confirmed in future, prospective, randomized studies to be the new gold standard.”
Dr. Cloughesy has received compensation from Merck as an consultant on its advisory board.