TY - JOUR
T1 - Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy
AU - Ioannou, Nikolaos
AU - Hagner, Patrick R.
AU - Stokes, Matt
AU - Gandhi, Anita K.
AU - Apollonio, Benedetta
AU - Fanous, Mariam
AU - Papazoglou, Despoina
AU - Sutton, Lesley Ann
AU - Rosenquist, Richard
AU - Amini, Rose Marie
AU - Chiu, Hsiling
AU - Lopez-Girona, Antonia
AU - Janardhanan, Preethi
AU - Awan, Farrukh T.
AU - Jones, Jeffrey
AU - Kay, Neil E.
AU - Shanafelt, Tait D.
AU - Tallman, Martin S.
AU - Stamatopoulos, Kostas
AU - Patten, Piers E.M.
AU - Vardi, Anna
AU - Ramsay, Alan G.
N1 - Publisher Copyright:
© 2021 by The American Society of Hematology.
PY - 2021/1/14
Y1 - 2021/1/14
N2 - 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).
AB - 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).
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U2 - 10.1182/blood.2020006073
DO - 10.1182/blood.2020006073
M3 - Article
C2 - 33024998
AN - SCOPUS:85099909729
SN - 0006-4971
VL - 137
SP - 216
EP - 231
JO - Blood
JF - Blood
IS - 2
ER -