Interleukin 1 Receptor Antagonist Protein study with OTHER data on dbGaP (17 participants)

phs003655 — Efficacy and Immune Effects of Anakinra Prophylaxis for Neurologic    Toxicity and Cytokine Release Syndrome in Patients with Lymphoma    Receiving Axicabtagene Ciloleucel

<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