Abstract A152: Investigating metabolic basis of neurotoxicity during CAR-T therapies

Chimeric antigen receptor T (CAR-T) cell therapies are rapidly becoming first in line therapies for treatment of hematologic malignancies. This is due to the efficacy of the treatment and long-lasting tumor responses. However, CAR-T therapies are associated with unique set of acute toxicities— cytokine release syndrome (CRS) and neurologic toxicities—the cause of which is not clear. As other immune therapies are becoming more widely used, these toxicities are observed in patients undergoing bispecific T-cell engaging antibodies (BiTEs) and checkpoint blockade therapies. Here, we sought to define metabolic changes in patients undergoing chimeric antigen receptor (CAR) T-cell therapy for B-acute lymphoblastic leukemia. We performed metabolic analysis of amino acids in serum samples, and identified significant up-regulation of tryptophan-kynurenine metabolism in patients with high-grade neurotoxicity. In-depth look at tryptophan-kynurenine pathway in cerebrospinal fluid patient samples determined quinolinic acid up-regulation to correlate with low- and high-grade neurotoxicity, indicating local production of this metabolite. We show that quinolinic acid is produced by activated monocytes and microglia in response to Il1beta and TNF. Importantly, tryptophan metabolite—kynurenine— stimulates Il1beta production and further activation of monocytes, possibly exacerbating CSR and neurotoxicity. This study suggests that inhibition of tryptophan-kynurenine pathway may offer some benefit to manage neurotoxicity and CRS associated with CAR-T-cell therapy treatment. Citation Format: Darin Salloum, Bianca Santomasso, Renier J. Brentjens, Hans-Guido Wendel. Investigating metabolic basis of neurotoxicity during CAR-T therapies [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A152.