Combinational Immunotherapy for Hepatocellular Carcinoma: Radiotherapy, Immune Checkpoint Blockade and Beyond

Lee, Yun Hua; Tai, David; Yip, Connie; Choo, Su Pin; Chew, Valerie

doi:10.3389/fimmu.2020.568759

Cited by 96 publications

(97 citation statements)

References 132 publications

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“…Lee et al. reviewed ( 25 ) that radiotherapy enhanced immune infiltrates into the tumor microenvironment (TME) but induced upregulation of immune checkpoint molecules (PD-1, PD-L1) and VEGF. Moreover, anti-VEGF therapy promoted normalization of vessel formation, which improved the efficacy of radiotherapy and further boosted infiltration of cytotoxic cells into TME.…”

Section: Discussionmentioning

confidence: 99%

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

Zhong

Peng

et al. 2021

Front. Oncol.

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BackgroundPrevious studies have explored cancer immunotherapy with radiotherapy or anti-angiogenic therapy, but no trials have reported a triple therapy approach. This study aimed to investigate safety and clinical outcome of PD-1/PD-L1 inhibitors combined with palliative radiotherapy and targeted angiogenesis therapy in hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage C.MethodsConsecutive patients (n=16) treated with PD-1/PD-L1 inhibitors combined with radiotherapy and anti-angiogenic therapy in a bi-institutional cohort between July 2017 and December 2020 were retrospectively included. Radiotherapy was conducted within 14 days of the first administration of immunotherapy. The primary endpoint was treatment-related adverse event (TRAE).ResultsThe median follow-up was 383 days. Fifteen patients (93.8%) experienced at least 1 TRAE. The most common TRAEs of any grade were rash (25%), diarrhea (25%), aspartate aminotransferase increase (18.8%), alanine transaminase increase (18.8%), decreased appetite (18.8%), and fatigue (18.8%). Grade 3/4 TRAEs occurred in 4 patients (25%) and finally led to treatment interruption. No patient death was attributed to treatment. No specific events were responsible for the addition of radiotherapy. Six patients showed partial response, 7 showed stable disease, and 2 showed progressive disease. The objective response rate and disease control rate were 40.0% (95% CI 16.3%–67.7%) and 86.7% (95% CI 59.5%–98.3%), respectively. Moreover, the median progression-free survival was 140 days. Patients had a median overall survival of 637 days, and the estimated rates of survival at 6 and 12 months were 92.3% and 75.5%, respectively.ConclusionPD-1/PD-L1 inhibitors combined with palliative radiotherapy and anti-angiogenic therapy appear to be safe, with no unexpected adverse events. Additional studies exploring the clinical benefit are warranted.

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Section: Discussionmentioning

confidence: 99%

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

Zhong

Peng

et al. 2021

Front. Oncol.

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“…103 Murine as well as clinical studies have shown that radiation can potentiate the cellular anti-cancer immune response by inducing cancer cell death and further sensitize tumors to ICIs. 104,105 In turn, the application of ICIs may revert radiation-induced exhaustion of cytotoxic T cells. 105,106 Based on the potential synergistic effects of percutaneous radiation and cancer immunotherapy, the combination of radiotherapy and ICIs is currently under investigation in HCC.…”

Section: Perioperative/interventional Therapymentioning

confidence: 99%

“…104,105 In turn, the application of ICIs may revert radiation-induced exhaustion of cytotoxic T cells. 105,106 Based on the potential synergistic effects of percutaneous radiation and cancer immunotherapy, the combination of radiotherapy and ICIs is currently under investigation in HCC. 105 Nevertheless, alongside initial response rates, long-term oncological outcomes and clinical safety need to be further evaluated.…”

Section: Perioperative/interventional Therapymentioning

confidence: 99%

The therapeutic landscape of hepatocellular carcinoma

Gallage

García‐Beccaria

Szydlowska

et al. 2021

Med

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The liver is endowed with an amazing regenerative capacity that allows it to withstand an enormous amount of damage. Nevertheless, it is precisely this highly regenerative capacity that renders it susceptible to dysplasia and liver cancer. Liver cancer is not only one of the most common cancers but also one of the deadliest. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for up to 70%-90% of all cases, but treatment options for advanced stages remain scarce. Therefore, a great deal of effort has gone into identifying early diagnostic markers as well as novel therapies, both local and systemic, for the treatment of this deadly disease. In this review, we aim to shed light into the current therapeutic landscape of HCC with an emphasis on the available treatments, ranging from surgical and local-ablative therapy for early and intermediate stages of the disease to systemic therapies for advanced cancer treatments. We will also address the molecular mechanisms and limitations of currently available systemic therapies and the causes of treatment resistance and finally summarize the emerging future avenues and novel concepts that are promising.

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“…Mounting evidence suggests local radiotherapy might promote immunogenic tumor cell death, and ICIs could favor a stronger immunologic anti-tumor reaction after treatment [ 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ]. Despite this, there is no published prospective clinical data on combined RT and ICIs therapy in HCC, except a few small series [ 134 ].…”

Section: Combination Of External Radiotherapy and Immunotherapymentioning

confidence: 99%

Stereotactic Radiotherapy for Hepatocellular Carcinoma, Radiosensitization Strategies and Radiation-Immunotherapy Combination

Pérez-Romasanta

Portillo

Rodríguez-Gutierrez

et al. 2021

Cancers

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Stereotactic body radiotherapy (SBRT) is an emerging ablative modality for hepatocellular carcinoma (HCC). Most patients with HCC have advanced disease at the time of diagnosis, and therefore, are not candidates for definitive-intent therapies such as resection or transplantation. For this reason, various alternative local and regional therapies have been used to prevent disease progression, palliate symptoms, and delay liver failure. Stereotactic body radiation therapy is a non-invasive technique of delivering ablative doses of radiation to tumors while sparing normal or non-tumor hepatic tissue. Incorporation of SBRT in multidisciplinary HCC management is gradual, initially applied when other liver-directed therapies have failed or are contraindicated, and tried in combination with other locoregional or systemic therapies for more unfavorable conditions by more experienced teams. In order to improve SBRT therapeutic ratio, there has been much interest in augmenting the effect of radiation on tumors by combining it with chemotherapy, molecularly targeted therapeutics, nanoparticles, and immunotherapy. This review aims to synthesize available evidence to evaluate the clinical feasibility and efficacy of SBRT for HCC, and to explore novel radio-potentiation concepts by combining SBRT with novel therapeutics. It is expected that those approaches would result in improved therapeutic outcomes, even though many questions remain with regard to the optimal way to assemble treatments. Further trials are needed to evaluate and consolidate these promising therapies for HCC.

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Combinational Immunotherapy for Hepatocellular Carcinoma: Radiotherapy, Immune Checkpoint Blockade and Beyond

Cited by 96 publications

References 132 publications

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

The therapeutic landscape of hepatocellular carcinoma

Stereotactic Radiotherapy for Hepatocellular Carcinoma, Radiosensitization Strategies and Radiation-Immunotherapy Combination

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