Abstracts vi95
NEURO-ONCOLOGY • NOVEMBER 2016endogenous TCR mechanisms. We developed CARs targeting the tumorspecific mutation, EGFRvIII, and found that antitumor efficacy against murine models of GBM required host preconditioning with total body irradiation prior to immunotherapy. Radiation-induced lymphopenia is believed to enhance the in vivo expansion profile and survival of T cells delivered intravenously by improving the bioavailability of homeostatic cytokines. Given the lymphodepleting effects of temozolomide (TMZ), we conducted studies to generate a clinically relevant and translatable treatment strategy for patients with GBM. Using the syngeneic GBM cell line, KR158B-Luc-EGFRvIII, we implanted tumor cells intracranially into mice and allowed tumors to engraft for 21 days to mimic disease at clinical presentation. Mouse equivalent doses of TMZ were generated based on the degree of lymphodepletion induced by standard (TMZSD) and dose-intensified (TMZDI) regimens routinely administered to patients in the clinic. CARs failed to induce antitumor responses when infused alone or following TMZSD; tumors exhibited growth kinetics similar to controls and there was no benefit in survival. In contrast, CARs administered after TMZDI induced complete regressions of these highly advanced brain tumors in >85% of mice as assessed by imaging and significantly enhanced survival. Mechanistically, TMZDI prompted a dramatic expansion of CARs and enhanced persistence in circulation and in the brain. Based on these findings, tumor-specific CARs may require TMZDI as first line chemotherapy in patients with GBM, as our results indicate that this regimen sufficiently enhances T-cell expansion and brain infiltration. Glioblastoma (GBM) is the most common and aggressive primary central nervous system cancer (CNS) in adults. Notably, biomarkers that stratify GBM patient survival are limited. Indoleamine 2,3-dioxygenase 1 (IDO1), an inducible tryptophan catabolic enzyme, has been shown to be a key mediator of tumor-induced immunosuppression in multiple settings. Here, we utilized the cancer genome atlas to investigate the correlation between IDO1 and overall survival (OS) in low grade glioma (LGG) and GBM patients, as well as non-CNS cancer. Multivariate Cox regression analysis found IDO1 mRNA levels to be an independent prognostic factor for survival, both in LGG (WHO grade II, III, P = 0.0115; HR = 1.68) and GBM (WHO grade IV, P = 0.0076; HR=1.82) patients. Interestingly, Pearson correlation analysis also identified significant associations between IDO1 and potently immunosuppressive mediators including PD-L1, PD-L2, PD-1, CTLA-4, STAT3, CD39, BTLA, Lag3, FoxP3 and FGL2, both in LGG and GBM (P < 0.01, respectively). Within GBM, IDO1 mRNA levels were higher in the cellular (1.398 ± 0.1257; P < 0.01) and necrotic zones (1.543 ± 0.1489; P < 0.01), when compared to the infiltrating (0.9303 ± 0.0786) and leading margins (0.9064 ± 0.1224). KaplanMeier analysis also demonstrated that high IDO1 mRNA levels predict decreased survival in pa...
