Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes; therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.

An immune-related gene signature for predicting survival and immunotherapy efficacy in hepatocellular carcinoma

“…could reinvigorate anti-tumor immunity [50]. Recently, nivolumab and pembrolizumab, two therapeutics against PD-L1/PD1, have been recently approved for subsequent-line therapy [51].…”

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

“…143,146 Most of the previous randomised clinical trials that tested the combination of systemic therapy and locoregional therapy for HCC, either concurrent or sequential, failed to demonstrate a survival benefit of combination therapy. [147][148][149][150][151][152][153][154][155] The post-randomisation confounding factors previously mentioned contributed greatly to the failure of these trials. About 10 to 20% of patients randomised to the locoregional therapy arm of the clinical trials could not receive the assigned treatment because of technical difficulties.…”

Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors

“…In human cancers, the presence of T SCM or T RM cells is associated with better survival, and two studies reported that these populations seem to be particularly mobilized during anti-PD-1 therapy [ 102 , 117 ]. The rationale of combining immunogenic therapies to ICPi led to several clinical trials testing different associations in multiple cancers [ 170 , 171 , 172 , 173 , 174 ]. While clinical studies tend to confirm, at least in some cancer types, the benefit that such combinations bring to patients, the results clearly indicate that improvements are still required to fully exploit the potential of combined therapies while limiting their immune-related toxicity.…”