Abstract
Chronic lymphocytic leukemia (CLL) is characterized by an acquired immune dysfunction. CLL cells affect the phenotype and function of the entire spectrum of innate and adaptive immune cells, including monocytes, T cells, and natural killer (NK) cells, leading to a tumor-supportive environment and reduced immunosurveillance. Novel immunotherapies like immune checkpoint blockade, bi- and tri-specific antibodies, and chimeric antigen receptor (CAR) T cells use the patients’ immune system to induce therapeutic responses. Although these novel immunotherapies showed impressive results in several B cell lymphomas, responses in CLL were often disappointing. The strong immunomodulatory effect of CLL is believed to play a pivotal role in the low response rates to these immunotherapeutic strategies. In this review, we summarize how CLL influences the function of non-malignant lymphocytes, with a special focus on T and NK cells, two important cellular mediators for immunotherapy. Secondly, we provide a short overview of the activity of several immunotherapeutics in CLL, and discuss how novel strategies may overcome the disappointing response rates in CLL.
Highlights
Chronic lymphocytic leukemia (CLL) is a malignancy characterized by the accumulation of cluster of differentiation 19 (CD19)+ CD5+ B cells in blood, lymph nodes, and bone marrow [1]
Agents like the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax are highly effective in CLL and induce deep remissions, in patients that relapse after chemotherapy [2,3]
We describe the known permutations in T and natural killer (NK) cells of CLL patients and how these changes affect the activity of immunotherapy with immune checkpoint inhibitors, bi- and tri-specific antibodies, and chimeric antigen receptor (CAR) constructs
Summary
Chronic lymphocytic leukemia (CLL) is a malignancy characterized by the accumulation of cluster of differentiation 19 (CD19)+ CD5+ B cells in blood, lymph nodes, and bone marrow [1]. Introducing chimeric antigen receptors (CAR) on the surface of cytotoxic cells redirects them toward tumor cells while simultaneously inducing immune activation, which was remarkably effective as a treatment in acute lymphoblastic leukemia (ALL) and, to a lesser extent, in NHL [13,14]. We describe the known permutations in T and NK cells of CLL patients and how these changes affect the activity of immunotherapy with immune checkpoint inhibitors, bi- and tri-specific antibodies, and CAR constructs. We give an overview of immunotherapies that are currently under investigation for CLL and their effectivity, thereby providing an outlook on the future of CLL therapy Both cell types simultaneously, target tumor cells for immune recognition, and showed activity in several non-Hodgkin lymphomas (NHL), like diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) [10,11,12]. Dysfunction of T cells could hamper T-cell responses which are required in immunotherapeutic strategies
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