Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy.

Abstract

Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

• Authors: Nikolaos Ioannou, Patrick R Hagner, Matt Stokes, Anita K Gandhi, Benedetta Apollonio, Mariam Fanous, Despoina Papazoglou, Lesley-Ann Sutton, Richard Rosenquist, Rose-Marie Amini, Hsiling Chiu, Antonia Lopez-Girona, Preethi Janardhanan, Farrukh T Awan, Jeffrey Jones, Neil E Kay, Tait D Shanafelt, Martin S Tallman, Kostas Stamatopoulos, Piers E M Patten, Anna Vardi, Alan G Ramsay
• Journal: Blood (Blood) Vol. 137 Issue 2 Pg. 216-231 (01 14 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 33024998 (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

• 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
• Antineoplastic Agents
• Immune Checkpoint Inhibitors
• Piperidones
• Quinazolinones
• Interferons

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Immunotherapy (methods)
• Interferons (immunology)
• Leukemia, Lymphocytic, Chronic, B-Cell (immunology)
• Lymphocyte Activation (drug effects)
• Mice
• Piperidones (pharmacology)
• Quinazolinones (pharmacology)
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects, immunology)
• Tumor Microenvironment (drug effects)
• Xenograft Model Antitumor Assays