Effects of ibrutinib on T-cell immunity in patients with chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL), a highly heterogeneous B-cell malignancy, is characterized by tumor microenvironment disorder and T-cell immune dysfunction, which play a major role in the proliferation and survival of CLL cells. Ibrutinib is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK). In addition to targeting B-cell receptor (BCR) signaling to kill tumor cells, increasing evidence has suggested that ibrutinib regulates the tumor microenvironment and T-cell immunity in a direct and indirect manner. For example, ibrutinib not only reverses the tumor microenvironment by blocking cytokine networks and toll-like receptor signaling but also regulates T cells in number, subset distribution, T-cell receptor (TCR) repertoire and immune function by inhibiting interleukin-2 inducible T-cell kinase (ITK) and reducing the expression of inhibitory receptors, and so on. In this review, we summarize the current evidence for the effects of ibrutinib on the tumor microenvironment and cellular immunity of patients with CLL, particularly for the behavior and function of T cells, explore its potential mechanisms, and provide a basis for the clinical benefits of long-term ibrutinib treatment and combined therapy based on T-cell-based immunotherapies.

ALK-Positive Anaplastic Large-Cell Lymphoma in a Patient with Chronic Lymphocytic Leukemia: A Case Report and Literature Review

“…This may partly due to compromised immunity, especially undermined T cell function in CLL. 30 Shared genetic aberrations with CLL may also alter clinical and biological characterization of ALCL, similar to the clonally related DLBCL. 31 Due to unavailability of ibrutinib, patients reviewed did not receive it in CLL treatment.…”

Targeting TP53 disruption in chronic lymphocytic leukemia: Current strategies and future directions

“…50 To address this, combining small molecules with CD19 CART cell immunotherapy has shown promise, with a recent study reporting a 3-month CR rate of 44% and 72% of patients showing undetectable MRD at 12 months. 51,52 Notably, ibrutinib may play a role in redirecting the immune response, favoring the expansion and maintenance of CAR T-cell populations. 53 Allogeneic CAR T-cell and CAR natural killer (CAR-NK) therapy, as an extension of adaptive therapy with CAR T-cell products, offers high antitumor efficacy and the advantage of being readily available "off-the-shelf," without extended manufacturing time.…”

“… 45–49 However, CLL patients often develop T‐cell dysfunction over time, characterized by altered cytokine secretion, exhaustion markers, decreased cytotoxicity of CD8+ T cells, and a shift toward an effector memory phenotype 50 . To address this, combining small molecules with CD19 CART cell immunotherapy has shown promise, with a recent study reporting a 3‐month CR rate of 44% and 72% of patients showing undetectable MRD at 12 months 51,52 . Notably, ibrutinib may play a role in redirecting the immune response, favoring the expansion and maintenance of CAR T‐cell populations 53 …”

Unraveling the Bone Tissue Microenvironment in Chronic Lymphocytic Leukemia

“…Moreover, the evidence that BTK is also expressed on many hematopoietic cells suggests that the huge success of the BTK inhibitors in CLL also appears to be related to its pleiotropic activity on cells of the tumor microenvironment [81][82][83]. It has been, for example, recognized that Ibrutinib reshapes the T-cell compartment in CLL toward improved antitumor function, potentially shifting Th2 vs. Th1 polarization in CLL patients [84,85]. Ibrutinib further reduces the expression of inhibitory receptors, such as PD1 [86].…”