Potential synergistic anti‐tumor activity between lenalidomide and sorafenib in hepatocellular carcinoma

Ou, Da-Liang; Chang, Chung‐Cheng; Jeng, Yung‐Ming; Lin, Yu‐Ju; Lin, Zhong‐Zhe; Gandhi, Anita K.; Liao, Sheng-Chieh; Huang, Ziming; Hsu, Chiun; Cheng, Ann‐Lii

doi:10.1111/jgh.12708

Cited by 15 publications

(13 citation statements)

References 38 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This leads to T cell activation, promotion of Th1 T cell differentiation, and repair of defects in immune synapse formation . We have also found that lenalidomide can enhance cytotoxic T cell activity in the tumour micro‐environment using an orthotopic liver cancer mouse model . The potential effects of lenalidomide on other immune cells remain undetermined, and many analogs of lenalidomide have been developed to pursue better immune‐modulatory efficacy …”

Section: Discussionmentioning

confidence: 89%

Lenalidomide as second‐line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy

Shao

Chen

et al. 2017

Aliment Pharmacol Ther

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 89%

Lenalidomide as second‐line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy

Shao

Chen

et al. 2017

Aliment Pharmacol Ther

View full text Add to dashboard Cite

show abstract

“…VEGF blockade can improve dendritic cell differentiation [11] and synergize with immunotherapy [12]. In preclinical models, lenalidomide enhanced the antitumor activity of sorafenib, presumably through immune modulation and increased CD8 + of tumor infiltrating lymphocytes (TILs) and decreased T regs among TILs [13]. …”

Section: Assessment Analysis and Discussionmentioning

confidence: 99%

Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

et al. 2016

View full text Add to dashboard Cite

Lessons Learned Combination therapies in patients with hepatocellular carcinoma can be associated with overlapping toxicity and are therefore poorly tolerated. Using sorafenib at the maximum tolerated dose can lead to a higher incidence of toxicities. Consequently, combination studies might evaluate sorafenib at alternative schedules or doses to improve tolerance, recognizing this could affect sorafenib efficacy. Although this combination was poorly tolerated, it does not exclude further evaluation of new-generation immunomodulator drugs or immune checkpoint inhibitors in the hope of optimizing tolerance and safety. Background. Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), and to date, no combination therapy has demonstrated superior survival compared with sorafenib alone. The immunosuppressive microenvironment in HCC is a negative predictor for survival. Lenalidomide is an immunomodulator and antiangiogenic agent, with limited single-agent efficacy in HCC. Based on these data, we designed a phase I study of sorafenib plus lenalidomide to determine the safety and preliminary antitumor activity of this combination. Methods. This was an open-label, phase I study with a 3+3 dose escalation/de-escalation design. The starting dose of sorafenib was 400 mg p.o. b.i.d. and of lenalidomide was 15 mg p.o. daily with a planned dose escalation by 5 mg per cohort up to 25 mg daily. Dose de-escalation was planned to a sorafenib dose of 400 mg p.o. daily combined with two doses of lenalidomide: 10 mg p.o. daily for a 28-day cycle (cohort 1) and 10 mg p.o. daily for a 21- or 28-day cycle (cohort 2). Patients with cirrhosis, a Child-Pugh score of A-B7, and no previous systemic therapy were eligible. Results. Five patients were enrolled. Their median age was 56 years (range 39–61), and the ECOG status was 0–2. Four patients were treated at dose level (DL) 1. Because of the poor tolerance to the combination associated with grade 2 toxicities, one more patient was treated at DL −1. No dose-limiting toxicity was observed as specified per protocol. The most common toxicities were nausea, anorexia, pruritus, elevated liver enzymes, and elevated bilirubin. Three patients experienced one or more of the following grade 3 toxicities: fatigue (DL 1), increased bilirubin (DL 1), skin desquamation (DL −1), and elevated transaminase levels (DL 1). The median duration of therapy was 1 cycle (range 1–3). All patients discontinued the study, 4 because of progressive disease and 1 by patient preference. The best confirmed response was progressive disease. The median progression-free survival was 1.0 month (95% confidence interval 0.9–2.8), and the median overall survival was 5.9 months (95% confidence interval 3.68–23.4). Conclusion. In our small study, the combination of lenalidomide and sorafenib was poorly tolerated and showed...

show abstract

“…Spheroids were harvested into the standard 96-well plates, and measured by MTT assay. The cell cycle distribution and extent of apoptosis were evaluated by staining the cells with propidium iodide (50 μg/mL) in the presence of RNase A (100 units/mL) and measured by flow cytometry [24]. For the colony formation assay, the cells were seeded into 6-well plates (6 × 10 3 cells/well) and maintained in medium for 14 days, with medium changes every 4 days.…”

Section: Establishment Of Pd-l1-expressing Mouse Liver Cancer Cellsmentioning

confidence: 99%

“…Tumor weights were measured after 21 days of treatment. At the end of treatment, blood samples were collected to measure hemogram and biochemistry, and formalin-fixed, paraffin-embedded tumor samples were collected for analysis of tumor apoptosis (transferase deoxytidyl uridine end labeling [TUNEL] assay), microvessel density, and tumor proliferation (immunohistochemical staining) [24]. To evaluate the roles of CD8+ T cells in the antitumor efficacy of anti-PD1 antibodies and sorafenib, CD8+ T cells were depleted by intraperitoneal injection of anti-CD8 antibody (clone 53-6.72) or isotype control antibody (clone 2A3 or HRPN) (Bio X Cell), respectively.…”

Section: Drug Treatment and Efficacy/safety Evaluationmentioning

confidence: 99%

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma

Lin

Hsu

et al. 2018

Liver Cancer

Self Cite

View full text Add to dashboard Cite

Background: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. Methods: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. Results: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. Conclusions: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.

show abstract

Potential synergistic anti‐tumor activity between lenalidomide and sorafenib in hepatocellular carcinoma

Abstract: Lenalidomide can enhance the anti-tumor effects of sorafenib in HCC through its immune modulatory effects, and CD8(+) TILs play an important role in the anti-tumor synergism.

Cited by 15 publications

References 38 publications

Lenalidomide as second‐line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy

Lenalidomide as second‐line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy

Phase I Study of Lenalidomide and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma

Contact Info

Product

Resources

About