Blocking the CD39/CD73 pathway synergizes with anti-CD20 bispecific antibody in nodal B-cell lymphoma
Bispecific antibodies (BsAb) have emerged as a leading treatment modality in patients suffering from B-cell non-Hodgkin’s lymphoma (B-NHL). However, treatment failure is common and may potentially be attributed to pre-existing or emerging T-cell exhaustion. CD39 catalyzes—together with CD73—the hydr...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e009245.full |
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| author | Carsten Müller-Tidow Peter Dreger Joseph Kauer Wolfgang Huber Clara Kolbe Berit Brinkmann Sascha Dietrich Tobias Roider |
| author_facet | Carsten Müller-Tidow Peter Dreger Joseph Kauer Wolfgang Huber Clara Kolbe Berit Brinkmann Sascha Dietrich Tobias Roider |
| author_sort | Carsten Müller-Tidow |
| collection | DOAJ |
| description | Bispecific antibodies (BsAb) have emerged as a leading treatment modality in patients suffering from B-cell non-Hodgkin’s lymphoma (B-NHL). However, treatment failure is common and may potentially be attributed to pre-existing or emerging T-cell exhaustion. CD39 catalyzes—together with CD73—the hydrolysis of immunogenic ATP into immunosuppressive adenosine and thus actively promotes an immunosuppressive micromilieu. Previously, we and others demonstrated that CD39+ T-cell subsets may have an adverse impact on the efficacy of T-cell-engaging immunotherapies. In this study, we applied an autologous ex vivo culture model of primary lymph node-derived T cells to investigate the potential of anti-CD39 or anti-CD73 blocking antibodies as T-cell enhancing combination partners of an anti-CD20 BsAb. Existing single-cell data of patient samples examined in this study were used to detect potential biomarkers predicting combination benefits. Combining anti-CD20 BsAb with anti-CD39 or anti-CD73 blocking antibodies induced synergistic effects on tumor cell killing, T-cell expansion and secretion of cytokines, including granzyme B, perforin, interleukin-10, interferon-γ, and tumor necrosis factor-α. We discovered that blockade of the CD39/CD73 pathway was particularly effective in patients with a high proportion of Programmed cell death protein 1 (PD-1)+ T-cell immunoglobulin and mucin-domain containing-3 (TIM3)+ exhausted T cells. Also, expression of CD39 in effector memory T cells indicated superior treatment benefit ex vivo. In summary, our study holds significant relevance as it introduces the combination of bispecific and anti-CD39 or anti-CD73 antibodies as a synergistic treatment approach in B-NHL, while also suggesting potential indicators to identify patients that might benefit from this treatment. |
| format | Article |
| id | doaj-art-3d1daa30d36f4a7fb52d242e05ab512f |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-3d1daa30d36f4a7fb52d242e05ab512f2025-01-31T22:15:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-009245Blocking the CD39/CD73 pathway synergizes with anti-CD20 bispecific antibody in nodal B-cell lymphomaCarsten Müller-Tidow0Peter Dreger1Joseph Kauer2Wolfgang Huber3Clara Kolbe4Berit Brinkmann5Sascha Dietrich6Tobias Roider72 Molecular Medicine Partnership Unit (MMPU), Heidelberg, Heidelberg, Baden-Württemberg, Germany1 Heidelberg University Hospital Department of Hematology Oncology and Rheumatology, Heidelberg, Germany1 Heidelberg University Hospital Department of Hematology Oncology and Rheumatology, Heidelberg, Germany2 Molecular Medicine Partnership Unit (MMPU), Heidelberg, Heidelberg, Baden-Württemberg, Germany1 Heidelberg University Hospital Department of Hematology Oncology and Rheumatology, Heidelberg, Germany1 Heidelberg University Hospital Department of Hematology Oncology and Rheumatology, Heidelberg, Germany2 Molecular Medicine Partnership Unit (MMPU), Heidelberg, Heidelberg, Baden-Württemberg, Germany1 Heidelberg University Hospital Department of Hematology Oncology and Rheumatology, Heidelberg, GermanyBispecific antibodies (BsAb) have emerged as a leading treatment modality in patients suffering from B-cell non-Hodgkin’s lymphoma (B-NHL). However, treatment failure is common and may potentially be attributed to pre-existing or emerging T-cell exhaustion. CD39 catalyzes—together with CD73—the hydrolysis of immunogenic ATP into immunosuppressive adenosine and thus actively promotes an immunosuppressive micromilieu. Previously, we and others demonstrated that CD39+ T-cell subsets may have an adverse impact on the efficacy of T-cell-engaging immunotherapies. In this study, we applied an autologous ex vivo culture model of primary lymph node-derived T cells to investigate the potential of anti-CD39 or anti-CD73 blocking antibodies as T-cell enhancing combination partners of an anti-CD20 BsAb. Existing single-cell data of patient samples examined in this study were used to detect potential biomarkers predicting combination benefits. Combining anti-CD20 BsAb with anti-CD39 or anti-CD73 blocking antibodies induced synergistic effects on tumor cell killing, T-cell expansion and secretion of cytokines, including granzyme B, perforin, interleukin-10, interferon-γ, and tumor necrosis factor-α. We discovered that blockade of the CD39/CD73 pathway was particularly effective in patients with a high proportion of Programmed cell death protein 1 (PD-1)+ T-cell immunoglobulin and mucin-domain containing-3 (TIM3)+ exhausted T cells. Also, expression of CD39 in effector memory T cells indicated superior treatment benefit ex vivo. In summary, our study holds significant relevance as it introduces the combination of bispecific and anti-CD39 or anti-CD73 antibodies as a synergistic treatment approach in B-NHL, while also suggesting potential indicators to identify patients that might benefit from this treatment.https://jitc.bmj.com/content/13/1/e009245.full |
| spellingShingle | Carsten Müller-Tidow Peter Dreger Joseph Kauer Wolfgang Huber Clara Kolbe Berit Brinkmann Sascha Dietrich Tobias Roider Blocking the CD39/CD73 pathway synergizes with anti-CD20 bispecific antibody in nodal B-cell lymphoma Journal for ImmunoTherapy of Cancer |
| title | Blocking the CD39/CD73 pathway synergizes with anti-CD20 bispecific antibody in nodal B-cell lymphoma |
| title_full | Blocking the CD39/CD73 pathway synergizes with anti-CD20 bispecific antibody in nodal B-cell lymphoma |
| title_fullStr | Blocking the CD39/CD73 pathway synergizes with anti-CD20 bispecific antibody in nodal B-cell lymphoma |
| title_full_unstemmed | Blocking the CD39/CD73 pathway synergizes with anti-CD20 bispecific antibody in nodal B-cell lymphoma |
| title_short | Blocking the CD39/CD73 pathway synergizes with anti-CD20 bispecific antibody in nodal B-cell lymphoma |
| title_sort | blocking the cd39 cd73 pathway synergizes with anti cd20 bispecific antibody in nodal b cell lymphoma |
| url | https://jitc.bmj.com/content/13/1/e009245.full |
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