Cell-free DNA and Single-Cell RNA Analysis Useful for Studying Treatment of Leptomeningeal Disease
Key findings
- Two open-label phase 2 clinical trials at Massachusetts General Hospital have demonstrated that immune checkpoint inhibitors (ICIs) can prolong survival in patients with leptomeningeal disease
- This study used cell-free DNA and single-cell RNA profiling of cerebrospinal fluid from 19 patients in those trials to investigate genomic features associated with trajectories of response to pembrolizumab and ipilimumab/nivolumab
- In a subset of patients, ICI treatment was associated with increased numbers and proliferation of CD8+ T cells and increased interferon-γ signaling and cytotoxicity in CD8+ T cells
- Interferon-γ response and antigen processing signatures in tumor compartments markedly increased immediately after the first ICI dose, although they then steadily decreased over time
- One patient showed evidence of adaptive selection of a less-immunogenic subclone over a more-immunogenic subclone that seemed to coincide with the development of acquired resistance to pembrolizumab
Immune checkpoint inhibitors (ICIs) revolutionized the treatment of chemotherapy-refractory metastatic solid tumors and have lately shown promise for central nervous system metastases. Massachusetts General Hospital researchers previously showed in two open-label phase 2 trials that ICIs improve survival in leptomeningeal disease (LMD):
Subscribe to the latest updates from Cancer Center Advances in Motion
- A trial of pembrolizumab found that 60% of patients were alive three months after enrollment and the median overall survival was 3.6 months
- In a trial of ipilimumab plus nivolumab, reported in Nature Communications, 44% of patients were alive at three months and the median overall survival was 2.9 months
In a related report, also published in Nature Communications, the team investigated cellular and molecular features associated with trajectories of patient responses in those trials. The work was jointly supervised by Priscilla K. Brastianos, MD, director of the Brain Metastasis Program at the Mass General Cancer Center, and Scott L. Carter, PhD, and Alex K. Shalek, PhD, of the Broad Institute of MIT and Harvard.
Methods
In both trials, blood and cerebrospinal spinal fluid (CSF) were drawn prior to each dose of ICI when clinically indicated and were sent for genomic analysis. In this paper, the researchers report on single-cell RNA and cell-free DNA sequencing of 13 pre-treatment and 24 post-treatment CSF samples from 19 patients, including nine patients sampled multiple times.
Liquid Tumor Microenvironment
ICIs modulated the immune microenvironment in the CSF of some patients, and these changes may have been associated with clinical benefits:
- CD8+ T cells were more abundant and/or proliferative in samples treated with ICIs than in untreated samples
- Interferon-γ signaling and cytotoxicity in CD8+ T cells were higher after treatment
Potential Prognostic Value of ICI Response
Interferon-γ response and antigen processing signatures in tumor compartments markedly increased immediately after the first ICI dose, followed by a steady decrease over time. This suggests the magnitude of the initial inflammatory response by malignant cells may have prognostic value.
However, this result also hints at the potential limited efficacy of ICIs for LMD.
Adaptive Selection
One patient showed evidence of adaptive selection of a less-immunogenic subclone over a more-immunogenic subclone that seemed to coincide with the development of acquired resistance to pembrolizumab.
Overall, the study supports the clinical utility of cell-free and single-cell genomic measurements for LMD research and emphasizes the value of longitudinal profiling.
view original journal article Subscription may be required
Learn more about the Mass General Cancer Center
Refer a patient to the Mass General Cancer Center