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Simple Summary  Patients with chronic lymphocytic leukemia (CLL), the most frequent B cell malignancy in western countries, develop a progressive immunosuppression, leading to diminished anti-tumor immunity. Within the last years, immune checkpoint blockade has revolutionized anti-cancer therapies. Nonetheless, patients with CLL failed to achieve clinical benefits from therapies targeting widely-studied checkpoints such as PD-1/PD-L1 or CTLA-4. In this context, our results provide new insights about LAG-3 expression dysregulation in CLL and its role promoting tumor escape. Our data suggest that increased LAG-3 expression on leukemic cells correlates with shorter time to treatment and poor outcome in CLL. Moreover, treatment with relatlimab, a novel anti-LAG-3 blocking monoclonal antibody currently under clinical trial for different solid and hematological malignancies including CLL, restored, at least in part, NK and T cell-mediated anti-tumor responses. Altogether, our data provide the rationale to further investigate the role of LAG-3 in the pathogenesis of CLL.Abstract  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.

LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia