Central Nervous System
PV QA 2 - Poster Viewing Q&A 2
Purpose/Objective(s): Long-term outcomes for patients with glioblastoma multiforme (GBM) remain poor despite aggressive trimodal therapy. Imaging studies have a minimal role in early prediction of tumor response. Recent data suggest combined immunotherapy and stereotactic radiosurgery can produce a survival improvement in a murine glioma model, representing a promising treatment option for patients with GBM. The aim was to evaluate GBM tumor response to SRS in combination with immunotherapy. We also sought to identify radiographic and immunologic markers that may be predictive of early and long-term tumor control.
Materials/Methods: Adult male C57 mice were transplanted with murine glioma cells (GL261) in the frontal lobe. There were 4 experimental groups (n=7 per group): Naïve control (no tumor), no treatment (tumor-bearing control), radiation treatment (RT) alone (single dose 10 Gy given at 10 days after tumor implantation), and combined RT plus anti-PD-1 treatment (3 doses of anti-mouse PD-1; 10mg/kg i.p. at days 10, 12 and 14 after tumor implantation). Brain samples were collected at the time of death or at the end of the study duration (60 days). The samples were evaluated with pathologic analysis, immunohistochemical studies (IHC), and flow cytometry. Biospec 7.0 Tesla MRI scanner imaged the tumor with multiple sophisticated imaging parameters at 15, 30 and 45 days after implantation. Statistical comparisons were made using the log-rank Mantel Cox test and t-test.
Results: Outcomes were significantly improved in the combined treatment group. Median survival was >60 days for combined treatment, compared to 25 days for untreated mice, 30 days with anti-PD-1 monotherapy, and 36 days with 10 Gy RT alone (p<0.001). The combined treatment group showed complete pathological response in 75% of the mice, with median survival not reached over the study duration of 60 days. MRI analysis showed significant reduction of tumor size from combined treatment (p<0.05) and from RT alone (p<0.05), as compared to non-treated controls. Intratumoral apparent diffusion coefficient (ADC), T2 signal and cerebral blood flow (CBF) in the tumor-bearing region were significantly more heterogenous than contralateral normal brain (p<0.05). IHC and flow cytometry analysis revealed that the combined treatment produced a 3-fold increase in the number of CD45+ inflammatory cells. The ratio of polarized CD11b+/CD86+ macrophages/microglia increased significantly relative to the CD11b+/CD206+ counterparts in the tumor bearing region.
Conclusion: Single high dose radiation treatment in combination with immune checkpoint inhibition resulted in a prominent histologic response and improved survival in this murine GBM model. The enhanced tumor response was characterized by increased immune infiltration and favorable macrophage/microglia polarization, suggesting an immunogenic local tumor cell kill. Distinct multiparametric MRI signatures suggest the utility of early imaging biomarkers to predict treatment response.
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