Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma.

Abstract

Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory large B-cell lymphoma (LBCL). This study evaluated whether immune dysregulation, present before CAR T-cell therapy, was associated with treatment failure. Tumor expression of interferon (IFN) signaling, high blood levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and high blood interleukin-6 and ferritin levels were each associated with a lack of durable response. Similar to other cancers, we found that in LBCL tumors, IFN signaling is associated with the expression of multiple checkpoint ligands, including programmed cell death-ligand 1, and these were higher in patients who lacked durable responses to CAR-T therapy. Moreover, tumor IFN signaling and blood M-MDSCs associated with decreased axi-cel expansion. Finally, patients with high tumor burden had higher immune dysregulation with increased serum inflammatory markers and tumor IFN signaling. These data support that immune dysregulation in LBCL promotes axi-cel resistance via multiple mechanistic programs: insufficient axi-cel expansion associated with both circulating M-MDSC and tumor IFN signaling, which also gives rise to expression of immune checkpoint ligands.

• Authors: Michael D Jain, Hua Zhao, Xuefeng Wang, Reginald Atkins, Meghan Menges, Kayla Reid, Kristen Spitler, Rawan Faramand, Christina Bachmeier, Erin A Dean, Biwei Cao, Julio C Chavez, Bijal Shah, Aleksandr Lazaryan, Taiga Nishihori, Mohammed Hussaini, Ricardo J Gonzalez, John E Mullinax, Paulo C Rodriguez, Jose R Conejo-Garcia, Claudio Anasetti, Marco L Davila, Frederick L Locke
• Journal: Blood (Blood) Vol. 137 Issue 19 Pg. 2621-2633 (05 13 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 33512407 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• Biological Products
• Cytokines
• RNA, Neoplasm
• Receptors, Chimeric Antigen
• Ferritins
• Interferons
• axicabtagene ciloleucel

Topics

• Adult
• Aged
• Biological Products (immunology)
• Cytokines (blood)
• Female
• Ferritins (blood)
• Humans
• Immunotherapy, Adoptive
• Interferons (physiology)
• Lymphoma, B-Cell (genetics, immunology, therapy)
• Male
• Middle Aged
• Myeloid-Derived Suppressor Cells (immunology)
• RNA, Neoplasm (biosynthesis)
• Receptors, Chimeric Antigen
• Treatment Failure
• Tumor Burden
• Tumor Escape
• Young Adult