Abstract IA02: Diffuse large B-cell lymphoma and neurotoxicity following CAR-T cell immunotherapy: Contributing factors and blood-brain barrier impairment biomarkers
Authors: Vidal-Lartitegui Leticia , Herreros-Pomares Alejando , Cervera Raimundo , Simarro Silvia , Tébar Roberto , Hernani Rafael , Benzaquren Ana , Terol María Jose , Solano Carlos , Vidal-Vanaclocha Fernando 
Published: October 2024

Abstract
CD19 chimeric antigen receptor (CAR) T-cell therapy has demonstrated striking efficacy for the treatment of diffuse large B cell lymphoma (DLBCL). However, CAR T-cell efficacy and clinical outcome in advanced stage DLBCLs still have limitations, including phenotypic heterogeneity of lymphoma and morbidity of the immune effector cell- associated neurotoxicity syndrome (ICANS) in treated patients. Thus, it is of paramount importance to better understand how cancer cell determinants, patient’s immuno- inflammatory response phenotype, and cancer-patient interrelationships are contributing to CAR T-cell success versus failure. Given the contribution of integrin α4β1 (VLA-4) signalling to DLBCL chemo-immune resistance via cancer cell interaction with microenvironmental vascular cell adhesion molecule-1 (VCAM-1), we first determined the transcriptional phenotype of a patient cohort at advanced stage DLBCL using a TaqMan Low Density Array (TLDA) which combines VLA-4-regulated genes with immune checkpoint and cancer stem genes. This approach allowed us to identify by quantitative PCR patients with and without VLA-4-regulated DLBCL at risk of VCAM- 1-inducible chemo-immune resistance. In addition, VLA-4-regulated gene signature predicted tumor stage, and a Lasso regression analysis to enhance prediction accuracy enabled a prognostic risk score based on 13-gene signature, which correlated with patient’s overall survival. Next, a panel of 14 biomarkers associated to pathophysiological regulation of brain-hepatopulmonary axis was used to phenotype 25 advanced stage DLBCLs with and without ICANS after CAR T-cell therapy. In this case, a systemic neuro-inflammatory profiling was determined in blood collected one day prior to, and on days 1, 7 and 28 after CAR T-cell infusion using multianalyte plates and Luminex technology. Interestingly, brain-hepatopulmonary axis biomarkers sorted CAR T-cell treated DLBCL patients according to ICANS occurrence, suggesting blood-brain barrier disruption in ICANS patients. More importantly, circulating VCAM-1, which affects DLBCLs with VLA-4-regulated phenotype, directly correlated with BBB biomarkers NCAM and Contactin-1 and inversely with RANTES, PDGF-AB, neurogranin, TREM2 and BDNF when comparing blood levels prior to CAR T-cell treatment in DLBCLs with and without ICANS. These BBB disruption biomarkers predicted ICANS occurrence after CAR T-cells in patients with VLA-4-regulated phenotype. High plasma VCAM-1 has long been associated to poor prognosis in aggressive lymphomas and our results demonstrate that this may occur in patients with a DLBCL of VLA-4-regulated phenotype, which in combination with brain-hepatopulmonary axis biomarkers associated to VCAM-1, alerts on the risk of ICANS following CAR T-cells. These findings may be exploited to increase CAR T-cell efficacy in patients with advanced stage DLBCL.
Citation Format: Leticia Vidal-Lartitegui, Alejando Herreros-Pomares, Raimundo Cervera, Silvia Simarro, Roberto Tébar, Rafael Hernani, Ana Benzaquren, María Jose Terol, Carlos Solano, Fernando Vidal-Vanaclocha. Diffuse large B-cell lymphoma and neurotoxicity following CAR-T cell immunotherapy: Contributing factors and blood-brain barrier impairment biomarkers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr IA02.