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Ioannou, Nikolaos; Hagner, Patrick R; Stokes, Matt; Gandhi, Anita K; Apollonio, Benedetta; Fanous, Mariam; Papazoglou, Despoina; Sutton, Lesley-Ann; Rosenquist, Richard; Amini, Rose-Marie; Chiu, Hsiling; Lopez-Girona, Antonia; Janardhanan, Preethi; Awan, Farrukh T; Jones, Jeffrey; Kay, Neil E; Shanafelt, Tait D; Tallman, Martin S; Stamatopoulos, Kostas; Patten, Piers E M; Vardi, Anna; Ramsay, Alan G
Blood, 01/2021, Letnik: 137, Številka: 2Journal Article
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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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