Targeting Myeloid Cells to Mitigate Immune Effector Cell-Associated Neurotoxicity Syndrome in Large B-cell Lymphoma

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Project Summary The unprecedented efficacy of chimeric antigen receptor (CAR) modified T cells, for the treatment of patients with relapsed or refractory large B-cell lymphoma (LBCL), is limited by significant toxicities, with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) being reported in up to 90% and 70% of patient, respectively. While the biology of CRS has been extensively investigated and tocilizumab, a monoclonal antibody targeting the IL-6 receptor, is available for its treatment, ICANS is largely managed by a broad immunosuppressive strategy using corticosteroids, which may affect CAR T-cell function. To this regard, we found that early and higher cumulative dose of corticosteroids is associated with early progression and death after axi-cel, highlighting the need for development of novel and corticosteroid-sparing strategies that target the underlying mechanism of ICANS. Pre-clinical models show that IL-1 blockade through anakinra, an IL-1 receptor antagonist, can effectively mitigate ICANS. Our analysis of CAR-T-treated LBCL patients shows that serum IL-1 peaks within the first 7 days after axi-cel infusion. In addition, we also observed that the infusion product of patients who develop ICANS has higher frequency of myeloid cells (named ICANS- associated cells or IACs), which expressed multiple cytokine and chemokine genes including IL-1. Importantly, patients with IACs detected within their infusion products had higher levels of inflammatory cytokines in their serum including IL-1 following infusion compared to patients with no IACs. Taken together, these data provided rationale to evaluate anakinra as a prophylactic strategy to mitigate ICANS after CAR T-cell therapy. Our central hypothesis is that IL-1 blockade using anakinra, an IL-1 receptor antagonist, will reduce the frequency of ICANS in r/r LBCL patients treated with axi-cel without impacting CAR T-cell expansion or efficacy and, that the benefit of anakinra will be observed primarily in patients treated with CAR-T infusion products containing IACs. Our specific aims are: 1) to investigate the effects of anakinra on ICANS and CAR T-cell activity, and 2) to determine whether prophylactic anakinra mitigates production of inflammatory cytokines in patients receiving CAR-T products containing IACs. We will test this by comparing the rates of ICANS and clinical response rates between two cohorts of patients: (i) 20 patients treated with prophylactic anakinra following axi-cel therapy, and (ii) a contemporaneous cohort of 20 patients treated with axi-cel without anakinra prophylaxis. Serial peripheral blood samples will be analyzed to determine the effects of anakinra on CAR T-cell amplification and phenotype. Plasma cytokines and chemokines will be assessed by multiplex assays, to determine the effects on anakinra on inflammatory molecules. The infusion products will be analyzed by 24-color spectral flow cytometry and single cell RNA-sequencing to determine the frequency of IACs.