Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter registrational trial of axi-cel in patients with refractory, aggressive B-cell non-Hodgkin lymphoma. In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with a 76% objective response rate and 47% complete response. The incidence of Grade 3 and higher (Gr 3+) cytokine release syndrome (CRS) and neurologic events (NE) was 13% and 29%, respectively, in 93 patients with 1 month follow-up (Neelapu ASH 2016). We present novel immune signatures of Gr 3+ CRS and NE by analyzing the axi-cel-related biomarker profile in association with clinical outcomes. Methods: In this interim analysis of 62 patients, 44 serum analytes pre- and post-axi-cel treatment were measured via ELISA at multiple timepoints during the first month. The number of CAR+ cells in blood was determined by qPCR. Kinetics and association of these markers with CRS and NE were analyzed. The treatment-related profile was defined by analytes with at least double an increase over baseline in at least 50% of patients. These analytes were selected and evaluated for association with Gr 3+ CRS or NE. Immune signatures were determined based on p-values applied to peak or cumulative levels of analytes and adjusted for multiplicity (stepdown method). Results: Out of 44 analytes measured, 12 demonstrated an increase by double over baseline in at least 50% of patients. This axi-cel-related biomarker profile includes immune proliferative/modulating cytokines, pro-inflammatory cytokines, markers of myeloid activation, and chemokines. Markers with the highest median-fold increase were IFNγ (44x), IL-10 (31x), IL-6 (26x), IL-15 (20x), and GRZB (17x). These peaked within 7-14 days and generally returned to baseline within 1 month post-treatment. Within this panel of 12 analytes elevated post-axi-cel treatment, markers associated with Gr 3+ CRS (p<0.05) were IL-10, IL-6, IL-2Rα, IL-8, MCP-1, IFNγ, IL-1Rα, and IP-10. Markers associated with Gr 3+ NE (p<0.05) were IL-6, IL-15, IL-8, and MCP-1. Peak levels of CAR T cells in blood, occurring within 14 days post-infusion, were associated with Gr 3+ NE (p=0.02) but not Gr 3+ CRS (p=0.6). A majority of patients with Gr 3+ NE had only Gr 0-2 CRS (16/22) while nearly 50% of patients with Gr 3+ CRS had Gr 0-2 NE (5/11). Conclusions: Biomarker and clinical evaluation suggests mechanistic differences underlying CRS and NE following axi-cel treatment. While Gr 3+ NE was associated with CAR T cell expansion, Gr 3+ CRS was instead associated with a broader array of serum markers, many linked to systemic myeloid activation. Further understanding of these immune signatures may provide insight into managing AEs associated with anti-CD19 CAR T cell therapy. Citation Format: Frederick L. Locke, John Rossi, Xiaodong Xue, Sattva S. Neelapu, Daniel H. Ryan, Armin Ghobadi, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Patrick M. Reagan, Marika Sherman, Janice Nagatani, Xiao Zhang, Lynn Navale, William Y. Go, Jeff Wiezorek, Adrian Bot. Immune signatures of cytokine release syndrome and neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT020. doi:10.1158/1538-7445.AM2017-CT020