<p>Chimeric antigen receptor T cells have transformed the treatment of multiple hematologic malignancies, but are limited in application due to treatment-related toxicities. Cytokine release syndrome (CRS) and neurotoxicity (NT) are the primary toxicities associated with these therapies and are thought to be mediated by broad immune activation due to robust T-cell expansion. Current treatment of these toxicities utilize anti-IL-6 directed therapy and/or systemic glucocorticoids to mitigate the consequences of this complex inflammatory cascade. We sought to use anakinra, an <a href="https://www.ncbi.nlm.nih.gov/gene/3554">IL-1R</a> antagonist, as a prophylactic strategy to prevent clinically meaningful CRS/NT, defined as grade 2 or higher toxicity necessitating clinical intervention. Although our study, in line with others, demonstrated that IL-1R antagonism is insufficient to prevent such toxicities entirely, we were able to gain insight into the molecular immune signaling associated with breakthrough CRS &#x26; NT in the presence of anakinra prophylaxis using our scRNA dataset of patients treated with and without IL-1R antagonism. We demonstrate that <a href="https://www.ncbi.nlm.nih.gov/gene/3565">IL-4</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/3586">IL-10</a> anti-inflammatory pathways in infused CAR-T products of both anakinra and non-anakinra cohorts were negatively associated with grade 2+ toxicities. We also found that expression of <a href="https://www.ncbi.nlm.nih.gov/gene/3458">IFN-gamma</a> pathways and ligand-receptor activities, as well as cytokine levels of IFN-gamma and <a href="https://www.ncbi.nlm.nih.gov/gene/3627">CXCL10 </a>in CD14+ monocytes, were significantly enriched in patients with breakthrough toxicity in the anakinra cohort. This correlated with an increase in IFN-gamma in the peripheral blood of patients with breakthrough toxicities, among other cytokines. These data identify IFN-gamma as a potential key mechanism in the development of CAR-T cell-associated toxcities and suggest that this pathway is also targetable and not inhibited by anakinra alone. </p>

Efficacy and Immune Effects of Anakinra Prophylaxis for Neurologic    Toxicity and Cytokine Release Syndrome in Patients with Lymphoma    Receiving Axicabtagene Ciloleucel

Efficacy and Immune Effects of Anakinra Prophylaxis for Neurologic Toxicity and Cytokine Release Syndrome in Patients with Lymphoma Receiving Axicabtagene Ciloleucel

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