Neoadjuvant Pembrolizumab Improves Survival in Recurrent Glioblastoma
Summary: A UCLA-led clinical trial shows that giving an anti-PD-1 immunotherapy drug before surgery produces a stronger benefit than administering the same therapy after surgery for people with recurrent glioblastoma.
Source: UCLA
Key finding: A randomized, multi-center pilot study found that pembrolizumab (an anti-PD-1 immune checkpoint inhibitor) given prior to surgery significantly extended overall survival in patients with recurrent, surgically resectable glioblastoma compared with giving the drug only after surgery.
Background
Immunotherapy has transformed treatment for several advanced cancers by mobilizing the patient’s own immune system to attack tumor cells. Despite these successes in other malignancies, immunotherapies have shown limited benefit in glioblastoma, an aggressive primary brain tumor with poor prognosis. Median survival for many patients with recurrent glioblastoma has historically been measured in months, and meaningful advances in treatment have been scarce.
Study design and participants
The trial, led by investigators at UCLA and conducted across seven U.S. medical centers, enrolled 35 patients with recurrent glioblastoma whose tumors were considered surgically resectable. Participants were randomized to receive pembrolizumab either before surgery (neoadjuvant treatment) with continued doses after surgery, or only after surgery (adjuvant treatment).
Of the 35 patients, 16 were assigned to the neoadjuvant group and 19 to the adjuvant group. Researchers compared overall survival, tumor and blood immune responses, and gene-expression changes associated with treatment timing.
Results
Patients treated with pembrolizumab before surgery experienced a substantially longer average survival compared with those who received the drug only after surgery. The neoadjuvant group had an average survival of 417 days, whereas the adjuvant-only group averaged 228 days.
Biological analyses revealed that neoadjuvant PD-1 blockade activated immune pathways within the tumor, including upregulation of T cell– and interferon-γ–related gene expression, and led to expanded clonal populations of tumor-infiltrating T cells. In contrast, these intratumoral immune signatures were less evident in patients who received pembrolizumab only after tumor resection.
Mechanism and interpretation
The investigators propose that when pembrolizumab is given before surgery it restores function to antigen-specific T cells that are already present but suppressed within the tumor microenvironment. By activating those T cells in situ, the immune system can mount a local and systemic antitumor response. When treatment is delayed until after surgery, many tumor-infiltrating T cells are removed along with the tumor mass, reducing the opportunity for the drug to reinvigorate an existing intratumoral immune response.
Clinical significance and next steps
These findings are important because they provide the first clinical evidence that an immune checkpoint inhibitor can meaningfully benefit patients with malignant brain tumors when given in a neoadjuvant setting. The results suggest a new and testable strategy for integrating immunotherapy into glioblastoma care and for designing future clinical trials.
Investigators emphasize that this pilot trial was small and that the results must be replicated in larger studies. Ongoing work is exploring combinations of neoadjuvant PD-1 blockade with other immunotherapies, cancer vaccines, and additional checkpoint inhibitors to better define which patients are most likely to respond and which combinations produce the strongest, durable antitumor immunity.
Collaborators and funding
The trial was conducted at multiple centers, including UCLA, Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, Massachusetts General Hospital Cancer Center, Huntsman Cancer Institute, M.D. Anderson Cancer Center and UC San Francisco. The study’s senior authors include Robert M. Prins (UCLA) and Timothy F. Cloughesy (UCLA), with co-senior author Patrick Wen (Dana-Farber) and co-first author Aaron Y. Mochizuki (UCLA).
Funding: Support came from the National Institutes of Health Specialized Program of Research Excellence in Brain Cancer, the Parker Institute for Cancer Immunotherapy, the Cancer Research Institute, the Musella Foundation, the Ben and Catherine Ivy Foundation, the Uncle Kory Foundation, the Defeat GBM Program of the National Brain Tumor Society, the Ziering Family Foundation and Merck & Co. Research. In-kind support was provided by Adaptive Biotechnologies.
Abstract (Study summary)
The randomized, multi-institution trial evaluated neoadjuvant and adjuvant pembrolizumab in patients with recurrent, surgically resectable glioblastoma. Neoadjuvant PD-1 blockade, continued after surgery, produced a significant survival benefit compared with adjuvant PD-1 blockade alone. Neoadjuvant treatment correlated with intratumoral upregulation of T cell– and interferon-γ–related genes, enhanced T cell clonal expansion, decreased PD-1 expression on circulating T cells, and other immune changes not observed when the drug was given only after surgery. These results indicate that administering PD-1 blockade prior to surgical resection can enhance both local and systemic antitumor immunity and may offer a more effective approach for treating recurrent glioblastoma.