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Gregory J. Riely, MD, PhD
Gregory J. Riely, MD, PhD
Posted: Wednesday, February 19, 2025
Leptomeningeal brain metastases (LBM) represent a particularly aggressive and often fatal progression of non–small cell lung cancer (NSCLC). However, a novel treatment approach—featuring engineered allogeneic stem cells delivering oncolytic herpes simplex virus and single-chain variable fragment targeting the immune checkpoint PD-1—enhanced therapeutic outcomes by inducing immunogenic cell death and disrupting oxidative phosphorylation, which in turn made tumors sensitive to cisplatin, in a recent study. These findings were presented by Khalid Shah, MS, PhD, of Brigham and Women’s Hospital, and colleagues and published in the Journal of the National Cancer Institute. Further studies are needed to refine the treatment approach and scale from animal to human models, they acknowledged.
“Our results support that our dual stem cell–based immunotherapy delivered locally can ultimately improve clinical outcome in patients with NSCLC leptomeningeal brain metastases,” Dr. Shah noted in an institutional press release. “Our work continues to build on developing new mechanism-based therapies for difficult-to-treat tumors in the brain.”
RNA sequencing of patient samples revealed that NSCLC brain metastases exhibited lower immune cell infiltration and an increased presence of PD-1–positive exhausted T cells compared with primary lung tumors. Based on these findings, Dr. Shah and his team first created immune-competent LBM mouse models that mimic LBM in patient settings. To counteract immunosuppression, the scientists engineered allogeneic stem cells to secrete single-chain variable fragment anti–PD-1 to directly address the tumor microenvironment using their preclinical models.
Intrathecal delivery of these stem cells in preclinical LBM models significantly reduced tumor burden and extended overall survival compared with conventional systemic anti–PD-1 therapy. When the stems cells were further developed to deliver dual therapy with the addition of the oncolytic herpes simplex virus, the treatment induced immunogenic cell death, activated T-cell signaling, and disrupted oxidative phosphorylation.
Disclosure: For full disclosures of the study authors, visit academic.oup.com.
Journal of the National Cancer Institute
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