scholarly journals The New Immuno-Oncology-Based Therapies and Their Perspectives in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 238
Author(s):  
Philippe Merle
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Complete Response ◽  
Phase 3 ◽  
Long Survival ◽  
Systemic Therapies

Hepatocellular carcinoma is a poor prognosis tumor. Systemic therapies are frequently used due to frequent recurrences after surgical or radiologic treatments. Anti-angiogenic tyrosine kinase inhibitors have shown efficacy in monotherapy, but with very low rates of long survival and exceptional recovery. Immuno-oncology based on immune checkpoint inhibitors has revolutionized the systemic therapies since showing long survival rates without any tumor progression or recurrence for some patients in partial or complete response, and possibly for some patients in stable disease. However, the rate of responders under immuno-oncology monotherapy is too low to increase significantly the median overall survival of the treated patients. The immuno-oncology-based combinations with different types of immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 inhibitors such as nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, tremelimumab), or the association of immune checkpoint inhibitors plus anti-angiogenic agents (bevacizumab, lenvatinib, cabozantinib), have led to a breakthrough in the treatment of hepatocellular carcinoma. Indeed, the first phase-3 trial, combining atezolizumab with bevacizumab, has dramatically changed the outcome of patients. Data from several other types of combinations assessed in phase-3 trials are pending, and if positive, will drastically arm the physicians to efficiently treat the patients, and disrupt the current algorithm of hepatocellular carcinoma treatment.

scholarly journals Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Acquired Resistance ◽  
Survival Rates ◽  
Advanced Hepatocellular Carcinoma ◽  
Primary Resistance ◽  
Advanced Hcc

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.

scholarly journals Immune Checkpoint Inhibitors as Monotherapy or Within a Combinatorial Strategy in Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 21 (17) ◽  
pp. 6302
Author(s):  
Michela Guardascione ◽  
Giuseppe Toffoli
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Target Therapy ◽  
Antiangiogenic Agents ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc

In advanced-stage hepatocellular carcinoma (HCC), systemic treatment represents the standard therapy. Target therapy has marked a new era based on a greater knowledge of molecular disease signaling. Nonetheless, survival outcomes and long-term response remain unsatisfactory, mostly because of the onset of primary or acquired resistance. More recently, results from clinical trials with immune targeting agents, such as the immune checkpoint inhibitors (ICIs), have shown a promising role for these drugs in the treatment of advanced HCC. In the context of an intrinsic tolerogenic liver environment, since HCC-induced immune tolerance, it is supported by multiple immunosuppressive mechanisms and several clinical trials are now underway to evaluate ICI-based combinations, including their associations with antiangiogenic agents or multikinase kinase inhibitors and multiple ICIs combinations. In this review, we will first discuss the basic principles of hepatic immunogenic tolerance and the evasive mechanism of antitumor immunity in HCC; furthermore we will elucidate the consistent biological rationale for immunotherapy in HCC even in the presence of an intrinsic tolerogenic environment. Subsequently, we will critically report and discuss current literature on ICIs in the treatment of advanced HCC, including a focus on the currently explored combinatorial strategies and their rationales. Finally, we will consider both challenges and future directions in this field.

scholarly journals Transarterial Chemoembolization Improves Survival in Advanced Hepatocellular Carcinoma Patients Treated with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors

2021 ◽  
Author(s):  
Yue Hu ◽  
Tao Pan ◽  
Xi Cai ◽  
Quansheng He ◽  
Yubao Zheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinase ◽  
Immune Checkpoint ◽  
Transarterial Chemoembolization ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Tace Group

Abstract BackgroundThe survival benefit and safety of transarterial chemoembolization (TACE) for advanced Hepatocellular Carcinoma (HCC) patients treated with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) is unclear. We aimed to investigate the efficacy and safety of TACE combined with TKIs and ICIs the treatment of advanced HCC. MethodsIn this study, the conditions of 147 patients with advanced HCC who underwent TKIs plus ICIs treatment between July 2017 and April 2020 were evaluated. We divided these patients into the TACE group and non-TACE group based on whether they were treated with TACE during TKIs plus ICIs treatment, and compared their survival outcomes, especially overall survival (OS), and whether they were exposed to unexpected toxicities. ResultsIn this study, a total of 98 patients who underwent TACE during TKIs plus ICIs treatment were included in the TACE group, while the other 49 patients were included in the non-TACE group. According to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST), the objective response rate (ORR) of the TACE group was higher than that of the non-TACE group (ORR 74.5% vs. 40.8%, p ＜0.001). The OS of the TACE group was significantly longer than the non-TACE group (OS 19.3 months vs. 10.8 months, p = 0.010). The incidence of grade 3-4 toxicities in the TACE group was similar to that in the non-TACE group (33.7% vs. 28.6%, p = 0.532). ConclusionsThe TACE treatment combined with TKIs plus ICIs resulted in longer OS compared to the treatment of systemic TKIs plus ICIs without TACE during the process of advanced HCC.

scholarly journals The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 532
Author(s):  
Patrizia Leone ◽  
Antonio Giovanni Solimando ◽  
Rossella Fasano ◽  
Antonella Argentiero ◽  
Eleonora Malerba ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Chemotherapeutic Agents ◽  
Protein Kinase Inhibitors ◽  
Great Promise ◽  
Chronic Injury

Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials.

scholarly journals Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaozhun Huang ◽  
Lin Xu ◽  
Teng Ma ◽  
Xin Yin ◽  
Zhangkan Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
New Strategy

BackgroundNivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC.MethodBetween June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed.ResultsAll the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis.ConclusionThe combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.

scholarly journals Safety and Efficacy of Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Fei Yang ◽  
Jun Yang ◽  
Wei Xiang ◽  
Bin-Yan Zhong ◽  
Wan-Ci Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Immune Checkpoint ◽  
Transarterial Chemoembolization ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Safety And Efficacy

PurposeTo explore the safety and efficacy of transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of unresectable hepatocellular carcinoma (uHCC).Materials and MethodsFrom August 2019 to July 2020, patients who received TACE combined with ICIs and TKIs were retrospectively analyzed. Treatment-related adverse events (AEs) were recorded. The Kaplan–Meier method was used to estimate time to progression (TTP) and progression-free survival (PFS).ResultsIn total, 31 patients with uHCC were included. Eleven patients were classified as BCLC-C. Nineteen patients had multiple lesions, and the cumulative targeted lesions were 69 mm (range, 21-170 mm) according to mRECIST. Twenty-nine (93%) patients experienced at least one AE during the treatment. Four (12.9%) patients developed AEs of higher grade (grade≥3). The objective response rate (ORR) and disease control rate (DCR) were 64.5% and 77.4%, respectively. The median time to response was 7 weeks (range, 4-30 w), and the duration of response was 17.5 weeks (range, 2-46 w). From the first ICIs, TTP and PFS were 6.5 months (95% CI, 3.5-11) and 8.5 months (95% CI, 3.5-NE), respectively.ConclusionsTACE combined with ICIs and TKIs shows an acceptable safety profile and considerable efficacy in patients with HCC.

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