Ikaros degradation by mezigdomide reduces T-cell dysfunction and improves the efficacy of antimyeloma T-cell therapies
Abstract
T cell dysfunction is an important contributor to both multiple myeloma (MM) disease progression and failure of anti-myeloma chimeric antigen receptor (CAR) T cell and bispecific T cell engager (TCE) therapies. Overcoming T cell dysfunction is therefore key to improving MM patient outcomes. Immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs) have been observed to activate T cells, and more recently reduce T cell dysfunction, however the underlying mechanisms behind this are incompletely understood. Here, using bone marrow samples from MM patients, we demonstrate a significant reduction in dysfunctional T cell populations expressing exhaustion markers such as TIGIT, upon treatment with Mezigdomide. We further demonstrate the ability of Mezigdomide to improve T cell function and cytotoxicity in primary T cell models of T cell dysfunction and bispecific TCE therapy in vitro. Using concurrent ATAC-seq, ChIP-seq, HiC and RNA-seq in primary T cells treated with Mezigdomide, we demonstrate the novel role of transcription factor Ikaros in regulating an important T cell exhaustion gene TIGIT. Finally, we demonstrate the ability of Mezigdomide to enhance survival outcomes from anti-BCMA CAR-T therapy in vivo. Overall, our data show that Mezigdomide treatment improves anti-myeloma T cell therapy efficacy and reduces T cell dysfunction by abrogating Ikaros-mediated upregulation of exhaustion genes.
Article Details
Authors (24)
Lucia Y Chen
Oxford University Hospitals NHS Trust, Oxford, ENG, United Kingdom
Adolfo Aleman
Icahn School of Medicine at Mount Sinai, New York
Marta Larrayoz
Hsiling Chiu
Bristol-Myers Squibb, Summit, New Jersey, United States
Junfei Zhao
Oliver Van Oekelen
Icahn School of Medicine at Mount Sinai, New York
Geoffrey Kelly
Seunghee Kim-Schulze
Alessandro Laganà
Icahn School of Medicine at Mount Sinai, New York
Sundar Jagannath
Icahn School of Medicine at Mount Sinai, New York
Tracy T. Chow
Bristol-Myers Squibb, Summit, New Jersey, United States
Teresa Lozano
Centro de Investigación Médica Aplicada, CIMA, Pamplona, Spain
Juan J Lasarte
Centro de Investigación Médica Aplicada, CIMA, Pamplona, Spain
Joseph C. Hamley
1Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
Warren Baker
University of Oxford, Oxford, United Kingdom
Benjamin L Ebert
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Udo Oppermann
University of Oxford, Oxford, United Kingdom
Michael D Amatangelo
Bristol-Myers Squibb, Madison, New Jersey, United States
Anita Krithivas Gandhi
Bristol-Myers Squibb, Madison, New Jersey, United States
Patrick Ryan Hagner
Bristol-Myers Squibb, Summit, New Jersey, United States
Jose A Martínez-Climent
Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Sarah Gooding
University of Oxford, Oxford, United Kingdom
Thomas A Milne
University of Oxford, Oxford, United Kingdom
Samir Parekh
Icahn School of Medicine at Mount Sinai, New York