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A large clinical trial has shown that pembrolizumab (Keytruda), an immunotherapy drug, nearly doubles the cancer-free survival time for patients with high-risk, muscle-invasive bladder cancer following surgery. The study, published on September 15, 2024, in The New England Journal of Medicine, was led by NIH researchers and demonstrated that pembrolizumab outperforms traditional observation methods post-surgery. Patients receiving pembrolizumab had a median cancer-free survival of 29.6 months, compared to 14.2 months for the observation group.
The trial enrolled 702 participants, some of whom had previously undergone cisplatin-based chemotherapy (neoadjuvant therapy). Pembrolizumab was administered every three weeks for a year. The drug was well tolerated, with common side effects including fatigue, itching, diarrhea, and thyroid issues.
Interestingly, the benefit of pembrolizumab was seen regardless of the tumor’s PD-L1 status.
Patients with PD-L1-positive tumors had a median cancer-free survival of 36.9 months.
Patients with PD-L1-negative tumors experienced 17.3 months cancer-free.
These results suggest that PD-L1 status should not be the sole factor in selecting patients for this therapy.
While overall survival rates were similar between the pembrolizumab and observation groups, many patients in the observation group began taking nivolumab once it was approved, complicating survival comparisons. Researchers are continuing to explore other treatment combinations and biomarkers to better personalize adjuvant therapy for bladder cancer patients.
Immunotherapy may help in glioblastoma survival, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. But, in a glimmer of hope, a recent study found that a drug designed to unleash the immune system helped some patients live longer. Glioblastoma powerfully suppresses the immune system, both at the site of the cancer and throughout the body, which has made it difficult to find effective treatments. Such tumors are complex and differ widely in their behavior and characteristics.
A small randomized, multi-institution clinical trial was conducted and led by researchers at the University of California at Los Angeles involved patients who had a recurrence of glioblastoma, the most common central nervous system cancer. The aim was to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab (checkpoint inhibitor) in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone.
Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhanced both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
Immunotherapy has not proved to be effective against glioblastoma. This small clinical trial explored the effect of PD-1 blockade on recurrent glioblastoma in relation to the timing of administration. A total of 35 patients undergoing resection of recurrent disease were randomized to either neoadjuvant or adjuvant pembrolizumab, and surgical specimens were compared between the two groups. Interestingly, the tumoral gene expression signature varied between the two groups, such that those who received neoadjuvant pembrolizumab displayed an INF-γ gene signature suggestive of T-cell activation as well as suppression of cell-cycle signaling, possibly consistent with growth arrest. Although the study was not powered for efficacy, the group found an increase in overall survival in patients receiving neoadjuvant pembrolizumab compared with adjuvant pembrolizumab of 13.7 months versus 7.5 months, respectively.
In this small pilot study, neoadjuvant PD-1 blockade followed by surgical resection was associated with intratumoral T-cell activation and inhibition of tumor growth as well as longer survival. How the drug works in glioblastoma has not been totally established. The researchers speculated that giving the drug before surgery prompted T-cells within the tumor, which had been impaired, to attack the cancer and extend lives. The drug didn’t spur such anti-cancer activity after the surgery because those T-cells were removed along with the tumor. The results are very important and very promising but would need to be validated in much larger trials.
2012pharmaceutical
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