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


Authors: Ioannou, N.; Hagner, P. R.; Stokes, M.; Gandhi, A. K.; Apollonio, B.; Fanous, M.; Papazoglou, D.; Sutton, L. A.; Rosenquist, R.; Amini, R. M.; Chiu, H.; Lopez-Girona, A.; Janardhanan, P.; Awan, F. T.; Jones, J.; Kay, N. E.; Shanafelt, T. D.; Tallman, M. S.; Stamatopoulos, K.; Patten, P. E. M.; Vardi, A.; Ramsay, A. G.
Article Title: 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. (Blood. 2021;137(2):216-231). © 2021 by The American Society of Hematology.
Journal Title: Blood
Volume: 137
Issue: 2
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2021-01-14
Start Page: 216
End Page: 231
Language: English
DOI: 10.1182/blood.2020006073
PUBMED: 33024998
PROVIDER: scopus
PMCID: PMC7820876
DOI/URL:
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
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  1. Martin Stuart Tallman
    649 Tallman