Background: Cytokine release syndrome (CRS) is a life-threatening complication of effective immunotherapies, particularly chimeric antigen receptor (CAR) T-cells. CRS is characterized by fever, hypotension, cardiac dysfunction, and at times end organ dysfunction and is mediated by elevated cytokines including IL-6, IFN-γ, and TNFα. A mainstay treatment for severe CRS is intravenous (IV) tocilizumab, a humanized, monoclonal antibody against membrane-associated and soluble IL-6 receptor. Most CRS symptoms resolve within hours of a single dose of IV tocilizumab in contrast to neurotoxicities, which are exacerbated or develop de novo after tocilizumab by a mechanism that is not well understood. IL-6 is elevated in the cerebrospinal fluid (CSF) of patients with CRS and neurotoxicity. The CSF penetration of tocilizumab is unknown. The objective of this study is to determine the CSF penetration of tocilizumab after IV administration in a nonhuman primate model.

Methods: Four adult male rhesus monkeys (Macaca mulatta) each received 10 mg/kg tocilizumab IV (human equivalent dose of 8 mg/kg). The macaques have an implanted CNS ventricular reservoir for CSF collection and two central venous lines; one for drug administration and a second for sample collection. Serial, paired blood and CSF samples were collected 0-8 hours, 1-3 days, 5 days, & 10 days post-infusion. A fluorescence bridging ELISA was used to determine serum and CSF levels of free tocilizumab (AbD Serotec).

Results: Three of the four animals were evaluable. Mean serum Cmax = 1.55 μM (1.20-2.13) and mean CSF Cmax = 0.00065 μM (0.00037-0.00083). Mean serum and CSF Tmax were 10 hours and 48 hours, respectively. Mean serum and CSF half-life were 127 and 339 hours, respectively. Serum AUC (mean) = 63 μM/hour (25-130) while CSF AUC (mean) = 0.099 μM/hour (0.07-0.125). CSF penetration was low with mean CSF:plasma AUC ratio of 0.26%. All samples and standards were plated in triplicate and had a coefficient of variation less than 20%. In one animal, tocilizumab concentrations were markedly lower with no detectable tocilizumab in the serum after 4 hours; results from this study were considered unevaluable.

Conclusion: Studies in this nonhuman primate model reveal low CSF penetration of tocilizumab and delayed time to maximum concentration in the CSF, potentially explaining the persistent neurologic toxicity observed in patients with CRS treated with tocilizumab. However, tocilizumab has a long half-life in the CSF, suggesting alternate means of delivery may be beneficial. Free tocilizumab concentrations were extremely low in one out of four animals and may have been due to preexisting inhibitors. Intranasal delivery of tocilizumab may result in significantly higher CSF exposure and provides a convenient route in patients that are otherwise critically ill. Studies of intranasal tocilizumab are ongoing and will be presented.

Citation Format: Anandani Nellan, Nalini Jayaprakash, Cindy McCully, Brigitte C. Widemann, Daniel W. Lee, Katherine E. Warren. Plasma and cerebrospinal fluid pharmacokinetics of tocilizumab in a nonhuman primate model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1411.