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

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, Preeti Janardhanan, Farrukh T. Awan, Jeffrey Jones, Neil E. Kay, Tait D. Shanafelt, Martin S. Tallman, Kostas Stamatopoulos, Piers E.M. PattenAnna Vardi, Alan G. Ramsay

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)216-231
Number of pages16
Issue number2
Early online date6 Oct 2020
Publication statusPublished - 14 Jan 2021


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