Abstract
The systemic treatment landscape for advanced hepatocellular carcinoma (HCC) has experienced tremendous paradigm shift towards targeting tumor microenvironment (TME) following recent trials utilizing immune checkpoint blockade (ICB). However, limited success of ICB as monotherapy mandates the evaluation of combination strategies incorporating immunotherapy for improved clinical efficacy. Radiotherapy (RT) is an integral component in treatment of solid cancers, including HCC. Radiation mediates localized tumor killing and TME modification, thereby potentiating the action of ICB. Several preclinical and clinical studies have explored the efficacy of combining RT and ICB in HCC with promising outcomes. Greater efforts are required in discovery and understanding of novel combination strategies to maximize clinical benefit with tolerable adverse effects. This current review provides a comprehensive assessment of RT and ICB in HCC, their respective impact on TME, the rationale for their synergistic combination, as well as the current potential biomarkers available to predict clinical response. We also speculate on novel future strategies to further enhance the efficacy of this combination.
Highlights
AND BACKGROUND ON CURRENT TREATMENT LANDSCAPE FOR Hepatocellular carcinoma (HCC)Liver cancer ranks second as the leading cause of cancer deaths in men and fourth highest cancer mortality in both genders globally with an estimate of 781,631 deaths in 2018 [1]
Greater efforts are required in discovery and understanding of novel combination strategies to maximize clinical benefit with tolerable adverse effects. This current review provides a comprehensive assessment of RT and immune checkpoint blockade (ICB) in HCC, their respective impact on tumor microenvironment (TME), the rationale for their synergistic combination, as well as the current potential biomarkers available to predict clinical response
Concordant to this finding, Chen et al showed in a separate study that responders to anti-PD-1 treatment have decreased expression levels of vascular endothelial growth factor A (VEGF-A) while the non-responders have increased VEFG-A expression [94]
Summary
Liver cancer ranks second as the leading cause of cancer deaths in men and fourth highest cancer mortality in both genders globally with an estimate of 781,631 deaths in 2018 [1]. The clinical benefit of the ICB in advanced HCC is notable with superior overall response rate (ORR) and fewer incidences of grade 3/4 treatment-related adverse events in both trials [17, 18] Another target of ICB is CTLA-4, an inhibitory receptor found on surface of T cells, which negatively modulates T cell activation and proliferation upon binding with B7 costimulatory molecule on APCs (Figure 2) [82]. In HCC, tumors with higher transcriptomic diversity were associated with worse OS in patients treated with ICB and these tumor cells expressed a significantly higher level of vascular endothelial growth factor A (VEGF-A) [95] Concordant to this finding, Chen et al showed in a separate study that responders to anti-PD-1 treatment have decreased expression levels of VEGF-A while the non-responders have increased VEFG-A expression [94].
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