Restoration of the immune function as a complementary strategy to treat Chronic Lymphocytic Leukemia effectively

Abstract

Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by uncontrolled proliferation of B-cells and severe immune dysfunction. Chemo(immuno)therapies (CIT) have traditionally aimed to reduce tumor burden without fully understanding their effects on the immune system. As a consequence, CIT are usually associated with higher risk of infections, secondary neoplasms and autoimmune disorders. A better understanding of the biology of the disease has led to the development of therapeutic strategies which not only act against malignant B-cells but also reactivate and enhance the patient’s own anti-tumor immune response. Here, we review the current understanding of the underlying interplay between the malignant cells and non-malignant immune cells that may promote tumor survival and proliferation. In addition, we review the available evidence on how different treatment options for CLL including CIT regimens, small molecular inhibitors (i.e, BTK inhibitors, PI3K inhibitors, BCL-2 inhibitors) and T-cell therapies, affect the immune system and their clinical consequences. Finally, we propose that a dual therapeutic approach, acting directly against malignant B-cells and restoring the immune function is clinically relevant and should be considered when developing future strategies to treat patients with CLL.

Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy

“…Moreover, ibrutinib has demonstrated the ability to restore immune competency, as it enhances the efficacy of chimeric antigen receptor T (CAR-T) cells in CLL, in which T cells undergo immune dysfunction [ 100 ]. There is also evidence that ibrutinib can help enhance the effectiveness of immune checkpoint inhibitors (ICI) through its action on ITK in CLL patients, restoring antitumor T-cell immune response [ 101 ]. These observations create an interesting rationale to combine different targeted and immunological therapies [ 102 , 103 ].…”

Ibrutinib Does Not Impact CCR7-Mediated Homeostatic Migration in T-Cells from Chronic Lymphocytic Leukemia Patients

“…Ibrutinib treatment exhibits profound effects on the immunocompromised T-cell compartment in CLL patients, among which the T-cell lymphocytosis stands out [ 1 , 18 , 19 , 38 ]. Theoretically, this effect might be a consequence of either an impaired trafficking to SLO or an increased egress from these tissues, although the exact mechanisms underlying this homeostatic change have only been partially tackled.…”

“…As a result, ibrutinib restores CLL T-cells deregulation [ 12 , 13 , 14 , 15 , 16 ], eventually modulating towards anti-tumor T-cell responses [ 17 , 18 ]. Today, several immunomodulatory mechanisms of ibrutinib on CLL T-cell homeostasis have been uncovered [ 19 ]; however, there are still many of them that we are only beginning to understand. This is the case of ibrutinib-induced CLL T-cell lymphocytosis that might stem from either an impaired trafficking to secondary lymphoid organs (SLO), and more specifically to lymph nodes (LN), or an increased egress from these tissues.…”

The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL)

“…Key elements of the microenvironment are monocyte-derived nurse-like cells (NLCs), mesenchymal stromal cells, T cells, NKT and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumour necrosis factor (TNF) family members and soluble factors ( Figure 1 ) [ 15 ]. CLL cells also promote the expansion and recruitment of immunosuppressive cells, including myeloid suppressor cells (MDSC) and T regulatory (Treg) cells, in order to escape from the control of the immune system [ 16 , 17 ]. Intriguingly, CLL clones often have features of regulatory B (Breg) cells.…”