CC-122 immunomodulatory effects in refractory patients with diffuse large B-cell lymphoma

Cubillos‐Zapata, Carolina; Avendaño-Ortíz, José; Arribas-Jiménez, Cristina; Hernández-Jiménez, Enrique; Toledano, Víctor; Villaescusa, Teresa; Moreno, Víctor; López-Collazo, Eduardo

doi:10.1080/2162402x.2016.1231290

Cited by 20 publications

(11 citation statements)

References 15 publications

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“…CC-122 is a novel immunomodulatory compound containing the conserved glutarimide for CRBN binding. As a derivative of thalidomide, CC-122 has pluripotent activities, including antitumor and modulation of immune cells [37,45]. CC-122 binds CRL4 CRBN E3 ligase to induce the degradation of IKZF1 and IKZF3 in MM cells, diffuse large B-cell lymphoma (DLBCL) cells and xenograft mouse models established from DLBCL cells [36,37].…”

Section: Cc-122 (Avadomide)mentioning

confidence: 99%

Novel immunomodulatory drugs and neo-substrates

2020

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Thalidomide, lenalidomide and pomalidomide are immunomodulatory drugs (IMiDs) effective in the treatment of multiple myeloma, myelodysplastic syndrome (MDS) with deletion of chromosome 5q and other hematological malignancies. Recent studies showed that IMiDs bind to CRBN, a substrate receptor of CRL4 E3 ligase, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in multiple myeloma cells, contributing to their anti-myeloma activity. Similarly, lenalidomide exerts therapeutic efficacy via inducing ubiquitination and degradation of CK1α in MDS with deletion of chromosome 5q. Recently, novel thalidomide analogs have been designed for better clinical efficacy, including CC-122, CC-220 and CC-885. Moreover, a number of neo-substrates of IMiDs have been discovered. Proteolysis-targeting chimeras (PROTACs) as a class of bi-functional molecules are increasingly used as a strategy to target otherwise intractable cellular protein. PROTACs appear to have broad implications for novel therapeutics. In this review, we summarized new generation of immunomodulatory compounds, their potential neo-substrates, and new strategies for the design of novel PROTAC drugs.

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Section: Cc-122 (Avadomide)mentioning

confidence: 99%

Novel immunomodulatory drugs and neo-substrates

2020

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“…As tumor immunosurveillance in patients with refractory DLBCL has shown diminished natural killer (NK) cell populations and cytotoxic activity, Cubillos-Zapata C et al [35] studied the modulatory and tumorsurveillance effects of CC-122 on the immune system of three DLBCL patients. Their data suggest that CC-122 treatment in DLBCL patients restores the innate immune response after discontinuing therapy.…”

Section: Cc-122mentioning

confidence: 99%

“…Sawas A et al [40] organized a phase 1/2 trial of ublituximab, in patients with relapsed/refractory B-NHL or CLL previously exposed to rituximab. 35 Patients with B-NHL (n = 27) and CLL (n = 8) had a median of 3 prior therapies are enrolled and received treatment of ublituximab. According to their research data ublituximab showed well-tolerated and effective responses in patients with heavily pre-treated.…”

Section: Ublituximabmentioning

confidence: 99%

Treatment strategies for diffusive large B-cell lymphoma

Linling¹,

Lingqing²,

Gu³

et al. 2018

Oncol Res Rev

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The treatment of diffusive large B-cell lymphoma (DLBCL) is generally based on multidrug chemotherapy, the association of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) has become the standard therapy for DLBCL since the 1970s. The outcome of DLBCL has been substantially enhanced by the addition of the anti-CD20 monoclonal antibody rituximab. However, there is still some patients failed to the first-line treatment, those were considered as relapsed/ refractory DLBCL, and thus we need to adjust the dose or change the therapeutics. In addition, different treatment strategies should be stratified according to age, the International Prognostic Index (IPI), performance status, stage, prognostic score and immunohistochemical biomarkers. Besides, many novel drugs are under investigation in DLBCL patients, especially CAR-T regimen will have great prospects for development.

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“…[1][2][3][4][5][6] CC-122 has multiple activities including immune modulation of several immune cell subsets such as T cells, B cells, monocytes, and natural killer cells, antigrowth activity in hepatocellular carcinoma (HCC), antiproliferative activity in multiple tumor types including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) represented by multiple cell lines and antiangiogenic activity as demonstrated by growth factor-induced endothelial cell migration and invasion, inhibition of endothelial cell sprout formation, and hypoxia-inducible factor-1α protein expression in vitro. 1,[7][8][9][10][11] As a result of these pharmacological effects, CC-122 as monotherapy and in combination with other agents is being evaluated as an oncology treatment for hematological malignancies including non-Hodgkin's lymphoma (NHL), FL, DLBCL, MM, and CLL, as well as advanced solid tumors, including glioblastoma multiforme and HCC. 4 In vitro studies showed that CC-122 was metabolized primarily via hydrolysis, oxidation, sulfation, or glucuronidation of the oxidative metabolites and a combination of the pathways.…”

mentioning

confidence: 99%

Single‐Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC‐122) in Subjects With Mild, Moderate, or Severe Renal Impairment

Li¹,

MacGorman²,

Liu³

et al. 2019

Clinical Pharm in Drug Dev

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CC-122 (Avadomide) is a nonphthalimide analogue of thalidomide that has multiple pharmacological activities including immune modulation of several immune cell subsets,antigrowth activity,antiproliferative activity,and antiangiogenic activity. CC-122 as monotherapy and in combination with other agents is being evaluated for multiple indications including hematologic malignancies and advanced solid tumors. Given that renal clearance is one of the major routes of elimination for CC-122 and its clearance/exposure could be affected by renal impairment, a total of 50 subjects with various degrees of renal function were enrolled in an open-label, single-dose study to evaluate the impact of renal impairment on CC-122 pharmacokinetic disposition. The study showed that following administration of a single oral dose of 3 mg CC-122, renal impairment reduced both the apparent total plasma clearance and renal clearance of CC-122, but it had less impact on CC-122 absorption, as demonstrated by similar T max and C max among groups with various degrees of renal function. Compared with exposure in subjects with normal renal function, total plasma exposure to CC-122 increased by ß20%, ß50%, and ß120% in subjects with mild, moderate, and severe renal insufficiency, respectively. Results from this study combined with modeling/simulation suggest that dose adjustments are necessary in patients with moderate or severe but not with mild renal impairment. Finally, a single dose of 3 mg CC-122 was safe and well tolerated by healthy subjects and subjects with mild, moderate, and severe renal impairment.

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CC-122 immunomodulatory effects in refractory patients with diffuse large B-cell lymphoma

Cited by 20 publications

References 15 publications

Novel immunomodulatory drugs and neo-substrates

Novel immunomodulatory drugs and neo-substrates

Treatment strategies for diffusive large B-cell lymphoma

Single‐Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC‐122) in Subjects With Mild, Moderate, or Severe Renal Impairment

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