SURG-49. INVESTIGATING LITT-BASED COMBINATION THERAPIES IN PRECLINICAL GLIOMA MODELS

Abstract

Abstract BACKGROUND Laser interstitial thermal therapy (LITT) is a minimally invasive means of tumor cyto-destruction with the potential for additional clinical benefits, such as altering the blood-brain barrier or the brain tumor microenvironment (TME). Using a murine model of GBM, we utilized a clinically relevant laser ablation model to identify and exploit immune TME changes after LITT to generate therapies that improve mouse survival, with the potential for rapid clinical translation. METHODS Right frontal lobe implantation of the immune “cold” SB28 murine glioma cells were performed in C57BL/6J mice. Tumor location was verified by MRI followed by stereotactic insertion of a paired fiberoptic laser and thermocouple to perform real-time hyperthermic ablation with temperature monitoring. Pulsed laser application maintained a peri-lesional temperature of 44°C for 150-180 seconds. Following LITT (or sham surgery), spectral flow cytometry was used to profile the immune TME. Survival studies were performed using a combination of LITT and immune modulating therapies. RESULTS Laser ablation alone provided a survival benefit compared to sham surgery (median survival: 29 vs 22.5 days, P<0.0001) in in glioma-bearing mice. Survival studies combining LITT with anti-PD1 lacked a significant response in the SB28 model but showed some long-term survivors. Flow cytometry performed on brain tissue post-LITT days 3 and 7 demonstrated little to no change in CD4+/CD8+ T cell responses but did show an increase in neutrophils, which expressed TLR2 and 4. The TME showed negligible numbers of phagocytic cells with obvious tumor cell uptake post-LITT. Using these results, we generated strategies for LITT-based combination immune therapies. Survival studies are ongoing using combinations of LITT/anti-PD1 with neutrophil depletion, inhibition of anti-CD47, and addition of broad TLR2/4 agonists as a neutrophil stimulus. CONCLUSIONS A clinically relevant immunocompetent murine LITT model enables the generation of novel treatment strategies with potential for rapid clinical translation.