期刊
BLOOD
卷 137, 期 2, 页码 216-231出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020006073
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资金
- Bristol-Myers Squibb
- British Society of Haematology
- Blood Cancer UK [14025]
- National Institutes of Health National Cancer Institute [RO1CA193541, U10CA180820, UG1CA232760, UG1CA233290]
Combination therapy of PD-1/PD-L1 with avadomide enhances anti-CLL activity by inducing T-cell signaling pathways and triggering T-cell responses, illustrating the importance of blockade-based combination therapy in sensitizing CLL to checkpoint therapy.
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 of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint illustrate the importance blockade-based combination therapy.
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