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

Research output: Contribution to journalArticlepeer-review

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. Patten & 2 more Anna Vardi, Alan G. Ramsay

Original languageEnglish
Pages (from-to)216-231
Number of pages16
JournalBlood
Volume137
Issue number2
Early online date6 Oct 2020
DOIs
Accepted/In press26 Sep 2020
E-pub ahead of print6 Oct 2020
Published14 Jan 2021

Bibliographical note

Funding Information: This work was supported by Bristol-Myers Squibb as part of a research collaboration, in addition to research charity support from the British Society of Haematology (fellowship, A.G.R.) and Blood Cancer UK (14025, A.G.R.). This study was coordinated in part by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer and Mitchell D. Schnall, Group cochairs) and supported by grants from the National Institutes of Health National Cancer Institute (RO1CA193541, U10CA180820, UG1CA232760, UG1CA233290). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Funding Information: This work was supported by Bristol-Myers Squibb as part of a research collaboration, in addition to research charity support from the British Society of Haematology (fellowship, A.G.R.) and Blood Cancer UK (14025, A.G.R.). This study was coordinated in part by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer and Mitchell D. Schnall, Group cochairs) and supported by grants from the National Institutes of Health National Cancer Institute (RO1CA193541, U10CA180820, UG1CA232760, UG1CA233290). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Publisher Copyright: © 2021 by The American Society of Hematology. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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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.

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