Clinical Trial, Phase II Journal Article Multicenter Study Ppublish 1 citation
PubMed: 39928957 DOI: 10.1182/bloodadvances.2024015161
Single-cell dynamics of breakthrough toxicities after anakinra prophylaxis for axicabtagene ciloleucel in lymphoma.
Blood Adv 9(9):2122-2135
Authors: Matthew J Frigault, Ning Yao, Trisha R Berger, Marc Wehrli, Kathleen M E Gallagher, Nora Horick, Charlotte E Graham, Caron A Jacobson, Yi-Bin Chen, Mark B Leick, Zachariah DeFilipp, Areej R El-Jawahri, P Connor Johnson, Maria Dolaher, Katelin Katsis, Austin I Kim, Jennifer Crombie, Reid W Merryman, Daniella Cook, Michael Trailor, Hana Cho, Richard Jeffrey, Rhine Shen, Simone Filosto, Jenny Nater, Gad Getz, Nicholas J Haradhvala, Marcela V Maus
Affiliations
- Cellular Immunotherapy Program, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA.
- Cancer Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.
- Harvard Medical School, Boston, MA.
- Dana-Farber Cancer Institute, Department of Hematology/Oncology, Boston, MA.
- Kite, a Gilead Company, Santa Monica, CA.
Abstract
Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy is limited by cytokine release syndrome (CRS) and neurotoxicity (NT). We sought to use once-daily prophylactic anakinra, an interleukin-1 (IL-1) receptor antagonist, to prevent CRS/NT that would require hospitalization (grade ≥2) in patients receiving axicabtagene ciloleucel for large-cell lymphoma, with the goal of facilitating outpatient therapy and management. Our study, in line with others, demonstrates that once-daily prophylactic anakinra is insufficient to prevent the development of toxicities that would require hospitalization in most patients. As part of the initial study design, we prospectively incorporated single-cell RNA sequencing to gain insight into the molecular immune signaling associated with breakthrough CRS and NT despite anakinra prophylaxis. In patients who developed breakthrough CRS or NT, we found that interferon gamma (IFN-γ) pathways and ligand-receptor activities were significantly enriched, as were cytokine levels of IFN-γ and CXCL10 in CD14+ monocytes. This correlated with increased IFN-γ and other cytokines in the peripheral blood. In infused CAR-T products, IL-4 and IL-10 anti-inflammatory pathways were negatively associated with grade ≥2 toxicities, regardless of anakinra treatment. These data identify IFN-γ as a potential key mechanism in CAR-T-associated toxicities, which is not inhibited by anakinra but may be otherwise targetable. This trial was registered at www.ClinicalTrials.gov as #NCT04150913.
MeSH
Cytokines, Interferon-Gamma, Cells, Hospitalization, Lymphoma, Interleukin-1, Therapeutics, Hematologic Diseases