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Triggering interfer...
Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1 /PD-1 immunotherapy
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- Ioannou, Nikolaos (author)
- Kings Coll London, Sch Canc & Pharmaceut Sci, Fac Life Sci & Med, London, England.
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- Hagner, Patrick R. (author)
- Karolinska Institutet,Bristol Myers Squibb, Summit, NJ USA.,Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Clin Genet, Stockholm, Sweden.
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- Stokes, Matt (author)
- Bristol Myers Squibb, Summit, NJ USA.
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- Gandhi, Anita K. (author)
- Bristol Myers Squibb, Summit, NJ USA.
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- Apollonio, Benedetta (author)
- Kings Coll London, Sch Canc & Pharmaceut Sci, Fac Life Sci & Med, London, England.
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- Fanous, Mariam (author)
- Kings Coll London, Sch Canc & Pharmaceut Sci, Fac Life Sci & Med, London, England.
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- Papazoglou, Despoina (author)
- Kings Coll London, Sch Canc & Pharmaceut Sci, Fac Life Sci & Med, London, England.
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- Sutton, Lesley-Ann (author)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
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- Rosenquist, Richard (author)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Clin Genet, Stockholm, Sweden.
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- Amini, Rose-Marie (author)
- Uppsala universitet,Klinisk och experimentell patologi,Univ Hosp, Uppsala, Sweden.
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- Chiu, Hsiling (author)
- Bristol Myers Squibb, Summit, NJ USA.
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- Lopez-Girona, Antonia (author)
- Bristol Myers Squibb, San Diego, CA USA.
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- Janardhanan, Preethi (author)
- Bristol Myers Squibb, San Diego, CA USA.
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- Awan, Farrukh T. (author)
- Ohio State Univ, Div Hematol, Ctr Canc, Columbus, OH 43210 USA.
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- Jones, Jeffrey (author)
- Bristol Myers Squibb, Summit, NJ USA.
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- Kay, Neil E. (author)
- Mayo Clin, Div Hematol, Rochester, MN USA.
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- Shanafelt, Tait D. (author)
- Stanford Univ, Sch Med, Stanford, CA 94305 USA.
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- Tallman, Martin S. (author)
- Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA.
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- Stamatopoulos, Kostas (author)
- Karolinska Institutet,Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
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- Patten, Piers E. M. (author)
- Kings Coll London, Sch Canc & Pharmaceut Sci, Fac Life Sci & Med, London, England.;Kings Coll Hosp NHS Fdn Trust, Dept Haematol, London, England.
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- Vardi, Anna (author)
- Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.;G Papanikolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanikolaou Hosp, HCT Unit, Thessaloniki, Greece.
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- Ramsay, Alan G. (author)
- Kings Coll London, Sch Canc & Pharmaceut Sci, Fac Life Sci & Med, London, England.
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Karolinska Institutet Kings Coll London, Sch Canc & Pharmaceut Sci, Fac Life Sci & Med, London, England (creator_code:org_t)
- American Society of Hematology, 2021
- 2021
- English.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 137:2, s. 216-231
- Related links:
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https://ashpublicati...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Klinisk laboratoriemedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Clinical Laboratory Medicine (hsv//eng)
Keyword
- Pathology
- Patologi
Publication and Content Type
- ref (subject category)
- art (subject category)
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Blood
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Ioannou, Nikolao ...
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Hagner, Patrick ...
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Stokes, Matt
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Gandhi, Anita K.
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Apollonio, Bened ...
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Fanous, Mariam
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Papazoglou, Desp ...
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Sutton, Lesley-A ...
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Rosenquist, Rich ...
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Amini, Rose-Mari ...
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Chiu, Hsiling
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Lopez-Girona, An ...
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Janardhanan, Pre ...
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Awan, Farrukh T.
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Jones, Jeffrey
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Kay, Neil E.
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Shanafelt, Tait ...
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Tallman, Martin ...
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Stamatopoulos, K ...
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Patten, Piers E. ...
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Vardi, Anna
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Ramsay, Alan G.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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- Articles in the publication
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Blood
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Uppsala University
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Karolinska Institutet