Csf Metabolomics As A Predictor Of Survival In Patients With Brain Metastasis Receiving Immunotherapy

Abstract INTRODUCTION Checkpoint inhibitors show a positive intracranial response in around 20–50% of patients with metastatic melanoma and non-small cell lung cancer (NSCLC). There is a current paucity of biomarkers to prospectively identify these patients. We hypothesize that CSF would provide useful data on tumor-related metabolites to help stratify responders and non-responders. We focused on adenosine and related nucleotides based on their role in creating an immunosuppressive tumor microenvironment. METHODS Fifty-one patients (43 with melanoma and 8 with NSCLC) received immunotherapies. The CSF samples from this cohort were compared to 30 controls and 60 non-immunotherapy-treated patients (13 with melanoma and 47 with NSCLC) using liquid chromatography/tandem mass spectrometry for quantitative assessment of metabolites. RESULTS The age and sex distribution were comparable in both cohorts. The most common immunotherapy regimens were ipilimumab, α-interferon and IL-2, while the most common non-immunotherapy regimens were carboplatin/taxol, carboplatin/pemetrexed and pemetrexed alone. CSF AMP, but not adenosine, ADP or ATP, from the immunotherapy cohort was higher in comparison to the non-immunotherapy cohort (P=0.0495). An adenosine/AMP ratio (AAR) was used to quantify relative adenosine production from AMP. AAR of 3.5–7 was associated with lower median survival from diagnosis of brain metastasis in immunotherapy-treated patients (9.1 months, log-rank P=0.0197). AAR below or above this range had significantly higher median survival (27.7 and 24.2 months, respectively). The same AARs could not stratify for survival in non-immunotherapy-treated patients (log-rank P=0.3039). Compared to the non-immunotherapy cohort, the immunotherapy cohort had higher kynurenine, glyceraldehyde 3-phosphate, pyruvate and lactate, as well as succinate, fumarate, malate, oxaloacetate, aconitate and isocitrate (all P< 0.05). CONCLUSION AAR of 3.5–7 could indicate an immunosuppressive microenvironment and needs further investigation to identify immunotherapy non-responders. The presence of elevated kynurenine, succinate, fumarate, malate and oxaloacetate suggests glutaminolysis related to immunotherapy. Research supported by the 2019 AACR-Bayer Innovation and Discovery Grant.