Treatment of Lymphoid and Myeloid Malignancies by Immunomodulatory Drugs

Abstract

Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

Catchet-MS identifies IKZF1-targeting Thalidomide analogues as novel HIV-1 latency reversal agents

“…We then examined proliferation potential upon iberdomide treatment alone or in combination with JQ-1. As previously reported in the literature, and consistent with their anti-lymphoproliferative capacity (Fuchs, 2019), we observed decreased proliferation capacity upon treatment of CD4+ and CD8+ primary T cells ( Figure 5G and H ; Supplementary Figure 10F and G ). Lastly, we assessed the effect of iberdomide on T cells functionality, by measuring cytokines IFNγ and IL-2 in CD4+ and CD8+ primary T cells.…”

“…The role of Thalidomide and its analogues in modulating the immune system has been very well studied and described in the past, in the context of lympho and myeloproliferative immune pathologies (57). Consistent with what is reported in the literature (57), in this study we show that Iberdomide and the FDA-approved Thalidomide analogue Pomalidomide modulate the proliferation capacity of primary T cells. In addition, we demonstrate that the use of Iberdomide does not affect T cell functionality, as measured by cytokine expression in CD4+ and CD8+ T cells and does not cause apoptosis or global immune activation.…”

“…Crucial to the potential applicability of Iberdomide treatment alone or in combination with other LRAs in future clinical studies is the absence of detrimental effects on the overall T cell biology and the preservation of a functional cytotoxic compartment. Interestingly, and consistent with its role as an immunomodulatory treatment for lymphoid and myeloid malignancies (Fuchs, 2019), we observed a reduction of T cell proliferative capacity after treatment with Iberdomide alone or in combination with JQ-1. Importantly, we demonstrate that the use of Iberdomide does not affect T cell functionality, as measured by cytokine expression in CD4+ and CD8+ T cells, and does not cause global immune activation.…”

Catchet-MS identifies IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents

“…Given the known immunomodulatory role of iberdomide and Thalidomide-derived drugs, we investigated the effects of iberdomide treatment alone or in combination with JQ-1 on T cell proliferation and functionality. As previously reported in the literature, and consistent with their anti-lymphoproliferative capacity ( 72 ), we observed decreased proliferation upon treatment of CD4 + and CD8 + primary T cells (Figure 4F and G ; Supplementary Figure S10D and E ). Finally, we assessed the effect of iberdomide on T cell functionality, by measuring cytokines IFNγ and IL-2 in CD4 + and CD8 + primary T cells.…”

Immunomodulatory Drugs in Acute Myeloid Leukemia Treatment

“…They have immunomodulatory and anti-proliferative properties and are applied in the treatment of several hematologic and solid malignancies as well as in autoimmune diseases [ 1 ]. IMiDs are the backbone of multiple myeloma therapies and recently their use has been extended to B-cell lymphomas and myelodysplastic syndromes (MDS) [ 2 ]. Recent studies have clarified the IMiDs mechanism of action.…”