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Targeting the tumor microenvironment in CLL
relapsed/refractory CLL. Similar to idelalisib, treatment with duvelisib entails increased risk of immune-related toxicities and infections in patients with CLL,62 likely also due to strong direct inhibitory effects on Treg and cytotoxic T-cell effector function as demonstrated in a CLL mouse model.63 In contrast, another next-generation PI3K inhibitor, umbralisib, with dual PI3Kδ/casein kinase-1-e (CK1e) inhibitory activity, did not modulate Treg function, which was associated with lower toxicity in a murine model.63 Thus, the disadvantageous direct effects of idelal- isib and duvelisib on T-cell subsets contributing to a risk of infections and toxicity, which have hampered their clinical usage, could potentially be mitigated with the use of umbralisib due to altered PI3K specificity. The most important effects of PI3K inhibition on the TME are sum- marized in Table 1 and illustrated in Figure 2.
BCL-2 inhibitors
The anti-apoptotic regulatory protein B-cell lymphoma 2 (BCL-2) is constitutively upregulated in several lym- phomas including CLL, hence playing a dominant role in blocking apoptotic signaling and promoting survival in these malignancies.64 Venetoclax (ABT-199), a selective BCL-2 inhibitor, demonstrated the ability to induce rapid
apoptosis in primary CLL cells in vitro and in xenograft models65 (Figure 3). In clinical trials, venetoclax alone or combined with an anti-CD20 antibody has achieved deep and durable undetectable minimal residual disease in patients with CLL.64,66 However, while leukemic cells are highly dependent on BCL-2, the dependence of non- leukemic cells on this protein seems to vary substantially. The high prevalence of grade 3/4 neutropenia among patients treated with venetoclax likely reflects the relative- ly marked dependency of granulopoiesis on BCL-2.67 T-cell homeostasis also depends on BCL-2, however with vari- able impact on different T-cell subsets. While murine naïve T cells were found to be highly dependent on BCL- 2, the protein was dispensable for memory T cells.68 Coherently, a decrease in naïve T-cell subsets and increased memory T cells have also been reported in both mice and healthy human subjects receiving venetoclax69 (Figure 3). A study on CLL patients treated with veneto- clax and the CD20 antibody obinutuzumab documented decreased numbers of normal B cells, NK cells, and T cells, including Tregs, in the peripheral blood. In addition, a decrease in the exhausted/chronically activated PD1+ T- cell phenotype was observed, along with improved NK- cell function, and reductions of the levels of elevated inflammatory cytokines70 (Figure 3). The authors interpret- ed these changes as being indirect effects due to eradica-
Figure 2. Effects of BTK inhibitors on the chronic lymphocytic leukemia tumor microenvironment. Inhibitory effects are represented by bars, stimulatory effects are represented by arrows. Upward arrows indicate increases, downward arrows indicate decreases. CLL: chronic lymphocytic leukemia; TME: tumor microenvironment; BTK: Bruton tyrosine kinase; BTKi: BTK inhibitor; ITK:interleukin-2-inducible T-cell kinase; PI3Kδ: phosphoinositide-3-kinase δ; TCR: T-cell receptor; CD: cluster of dif- ferentiation; CD40L: CD40 ligand; IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; PD-1: programmed cell death protein 1; Th: T helper; Treg: regulatory T cell; ADCP: antibody-dependent cellular phagocytosis; VCAM: vascular cell adhesion molecule; VLA, very late antigen; CXCL: CXC motif chemokine; MDSC: myeloid-derived suppressor cells.
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