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R. Svanberg et al.
tion of the leukemic cells, and any direct effects on these cells by venetoclax were not investigated. Critically, the TME also appears to play a role in venetoclax resistance. In a previous study, in vitro CD40/CD40L co-stimulation strongly reduced sensitivity to venetoclax through upreg- ulation of other anti-apoptotic proteins, such as myeloid cell leukemia 1 (MCL-1) and B-cell lymphoma extra large (BCL-XL), in CLL cells.71 The varying dependency on BCL- 2 among different microenvironmental cell types, as well as between patients, warrants further investigation, in order to optimize the advantages of targeting the apoptot- ic pathway in malignant cells, and utilize potential immunomodulatory effects in the immune TME while minimizing disadvantageous on-target-but-off-leukemic effects leading to adverse events.
Immunomodulatory drugs
Lenalidomide is an immunomodulatory drug (IMiD) widely used to treat multiple myeloma. Despite having no direct cytotoxicity against CLL cells in vitro,72 clinical activity in patients with CLL has been demonstrated,73,74 supporting anti-CLL immunomodulatory effects in the TME as a principle mode of action. In vitro, lenalidomide induces downregulation of CLL immune checkpoint receptors on T cells, suggesting treatment-induced immune activation or reversal of exhaustion.15 Moreover, lenalidomide treatment of autologous T cells and CLL cells triggers repair of T-cell dysfunction. This results in improved synapse formation, granzyme B- and IL-21- mediated cytotoxicity, enhanced CD8+ T-cell effector killing, and restored LFA-1-mediated T-cell motility.14,75–77 Supporting this, in vivo samples from treated patients revealed changes in the composition of the T-cell subpop- ulations and their cytokine production.78 Lenalidomide also affects CLL monocytes/NLC. The presence of lenalidomide impaired migration of CLL-supportive monocytes towards CCL2, CCL3, and CXCL12 in in vitro chemotaxis assays.79 The same study demonstrated downregulation of genes associated with pro-survival sig- nals for CLL cells and impaired protective ability of NLC.79 Moreover, CLL-induced immunosuppression was reversed by lenalidomide, with improved phagocytotic activity, cytokine production, T-cell stimulatory and pro- liferative activity.79 Lenalidomide has produced clinical responses as monotherapy,74 in combination with ritux- imab or with chemotherapy,80 and as maintenance fol- lowing chemotherapy.73 However, increased risk of toxic- ities and infections with treatment remains a concern,73 potentially reflecting potent activation of the immune TME with this class of drug. Thus, the place and dosing regimen for lenalidomide in clinical practice remain unclear. A novel option emerging for CLL therapy are next-generation cereblon E3 ligase modulators (CELMoD), with avadomide recently investigated in a preclinical study. Avadomide stimulated T-cell activation, the expression of immunostimulatory chemokines, and the formation of lytic synapses with CLL cells by trigger- ing inflammatory IFN type I and II signaling in previously exhausted T cells from patients.81 The potential and opti- mal roles of IMiD and CELMoD in the context of the CLL-TME remain to be determined; however, the favor- able immunomodulatory effects on the T-cell/NK-cell compartments imply a role for IMiD and CELMoD in
developing novel combination treatment strategies. The most important effects of IMiD/CELMoD on the TME are summarized in Table 1 and illustrated in Figure 3.
Immune checkpoint blockade
The PD-1:PD-L1 is an immune checkpoint pathway used by tumor cells to inhibit T cells and escape immune surveillance. Thus, this pathway constitutes an attractive therapeutic target (Figure 4).82 Blocking PD-L1 in CLL- transplanted mice resulted in repressed disease develop- ment and restored T-cell immune effector functions including improved cytotoxicity, cytokine production, and immune synapse formation.83 Despite this, the sparse clinical data on immune checkpoint blockade (ICB) in CLL are disappointing. In a phase II study of the PD-1 blocking antibody drug, pembrolizumab, four out of nine patients with Richter transformation showed clinical response to treatment, whereas none of the 16 CLL patients responded.84 The clinical efficacy of ICB-based therapy correlates with upregulated levels of tumor PD- L1 expression that is associated with an “inflamed” microenvironment with the presence of activated cyto- toxic tumor-infiltrating T cells attempting to engage tumor cells, which can be unleashed as checkpoint inhibitory signals are abrogated.85 PD-L1 expression on CLL cells is relatively low, likely reflecting low activity of cytolytic T cells.81,82 Furthermore, the immunosuppressive state of the TME in CLL, with profoundly exhausted effector T cells that exhibit multiple functional defects, likely contributes significantly to the lack of clinical response to checkpoint inhibitor monotherapy in CLL patients. Consistent with this, a recent study of patients’ lymph node biopsies has provided evidence for a non- inflamed microenvironment in CLL, incorporating low numbers of CD8+ T cells, low PD-L1 expression and pro- found T-cell exhaustion.81 Thus, strategies that can sub- vert the strong immunosuppressive pressure of the CLL- TME and overcome T-cell dysfunction may be necessary to sensitize CLL to ICB immunotherapy and develop therapeutic options for CLL patients. Further research to unravel the complex immunosuppression in the CLL- TME is warranted in order to develop and optimize immuno-oncology treatments.
T-cell-based therapy
Chimeric antigen receptor (CAR) T cells have emerged as a powerful therapeutic option designed to transfer high numbers of tumor-targeted effector T cells into the TME to overcome a paucity of endogenous cytolytic T cells. Briefly, autologous T cells are genetically modified to express CAR with specificity for specific tumor antigens, such as CD19 in B-cell malignancies, thus creating an adoptive T-cell-mediated cytotoxic response (Figure 4).86 CAR T cells combine the effects of T-cell and antibody- mediated immune responses by triggering T-cell activa- tion with granule exocytosis upon antigen binding.87 Despite the first successful CAR T-cell trial being reported in CLL, few clinical trials have subsequently reported effi- cacy of CAR T cells in CLL.88 CLL-induced T-cell dysfunc- tion, as well as understudied lymphoid TME barriers, likely reduce the efficacy of this approach in CLL. A
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haematologica | 2021; 106(9)