LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia
The inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignan...
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MDPI AG
2021-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/9/2112 |
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| author | Christian Sordo-Bahamonde Seila Lorenzo-Herrero Ana P. González-Rodríguez Ángel R. Payer Esther González-García Alejandro López-Soto Segundo Gonzalez |
| author_facet | Christian Sordo-Bahamonde Seila Lorenzo-Herrero Ana P. González-Rodríguez Ángel R. Payer Esther González-García Alejandro López-Soto Segundo Gonzalez |
| author_sort | Christian Sordo-Bahamonde |
| collection | DOAJ |
| description | The inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignancy. LAG-3 is an immune checkpoint receptor that negatively regulates T cell-mediated responses by inducing an hyporesponsive state, thus promoting tumor escape. Patients with chronic lymphocytic leukemia (CLL) develop a profound immune suppression that leads to lessened immunosurveillance and increased risk of developing a secondary neoplasia. In the study herein, we report the profound dysregulation of LAG-3 on leukemic cells in CLL. Likewise, natural killer (NK) and T cells showed increased LAG-3 expression, hence suggesting a role for this checkpoint in CLL-associated immunosuppression. High LAG-3 expression, as well as high levels of soluble LAG-3 (sLAG-3), correlated with adverse cytogenetics and poor outcome in patients with CLL, highlighting the clinical relevance of this immune checkpoint. Treatment of peripheral blood mononuclear cells (PBMCs) from patients with CLL with relatlimab, a new anti-LAG-3 blocking antibody currently evaluated in numerous clinical trials, depleted leukemic cells and restored NK cell- and T cell-mediated responses. Moreover, combination of LAG-3 with the immunomodulatory drug (IMiD) lenalidomide significantly increased IL-2 production by T cells and antibody-dependent cytotoxicity (ADCC) mediated by NK cells. Altogether, these data provide new insights into the potential anti-leukemic effects of relatlimab, currently in clinical trials in CLL, and provides the rationale to further investigate its combination with IMiDs for the management of hematological malignancies. |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:55:32Z |
| publishDate | 2021-04-01 |
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| series | Cancers |
| spelling | doaj.art-ebd43d1b5bb947539b9fc861b30c171f2023-11-21T17:23:56ZengMDPI AGCancers2072-66942021-04-01139211210.3390/cancers13092112LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic LeukemiaChristian Sordo-Bahamonde0Seila Lorenzo-Herrero1Ana P. González-Rodríguez2Ángel R. Payer3Esther González-García4Alejandro López-Soto5Segundo Gonzalez6Department of Functional Biology, Immunology, Universidad de Oviedo, 33006 Oviedo, SpainDepartment of Functional Biology, Immunology, Universidad de Oviedo, 33006 Oviedo, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006 Oviedo, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006 Oviedo, SpainDepartment of Hematology, Hospital de Cabueñes, 33203 Gijón, SpainInstituto Universitario de Oncología del Principado de Asturias (IUOPA), 33006 Oviedo, SpainDepartment of Functional Biology, Immunology, Universidad de Oviedo, 33006 Oviedo, SpainThe inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignancy. LAG-3 is an immune checkpoint receptor that negatively regulates T cell-mediated responses by inducing an hyporesponsive state, thus promoting tumor escape. Patients with chronic lymphocytic leukemia (CLL) develop a profound immune suppression that leads to lessened immunosurveillance and increased risk of developing a secondary neoplasia. In the study herein, we report the profound dysregulation of LAG-3 on leukemic cells in CLL. Likewise, natural killer (NK) and T cells showed increased LAG-3 expression, hence suggesting a role for this checkpoint in CLL-associated immunosuppression. High LAG-3 expression, as well as high levels of soluble LAG-3 (sLAG-3), correlated with adverse cytogenetics and poor outcome in patients with CLL, highlighting the clinical relevance of this immune checkpoint. Treatment of peripheral blood mononuclear cells (PBMCs) from patients with CLL with relatlimab, a new anti-LAG-3 blocking antibody currently evaluated in numerous clinical trials, depleted leukemic cells and restored NK cell- and T cell-mediated responses. Moreover, combination of LAG-3 with the immunomodulatory drug (IMiD) lenalidomide significantly increased IL-2 production by T cells and antibody-dependent cytotoxicity (ADCC) mediated by NK cells. Altogether, these data provide new insights into the potential anti-leukemic effects of relatlimab, currently in clinical trials in CLL, and provides the rationale to further investigate its combination with IMiDs for the management of hematological malignancies.https://www.mdpi.com/2072-6694/13/9/2112chronic lymphocytic leukemiaCLLLAG3relatlimabimmunotherapyimmune checkpoint |
| spellingShingle | Christian Sordo-Bahamonde Seila Lorenzo-Herrero Ana P. González-Rodríguez Ángel R. Payer Esther González-García Alejandro López-Soto Segundo Gonzalez LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia Cancers chronic lymphocytic leukemia CLL LAG3 relatlimab immunotherapy immune checkpoint |
| title | LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia |
| title_full | LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia |
| title_fullStr | LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia |
| title_full_unstemmed | LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia |
| title_short | LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia |
| title_sort | lag 3 blockade with relatlimab bms 986016 restores anti leukemic responses in chronic lymphocytic leukemia |
| topic | chronic lymphocytic leukemia CLL LAG3 relatlimab immunotherapy immune checkpoint |
| url | https://www.mdpi.com/2072-6694/13/9/2112 |
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