Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle

Abstract

Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises.

Protein and metabolic profiles of tyrosine kinase inhibitors co-resistant liver cancer cells

“…Many HCC patients may develop drug resistance or relapse shortly after receiving first-line drug treatment, leading to poor treatment outcomes ( Wang et al, 2024 ). The heterogeneity of HCC cells, their escape mechanisms, the existence of single nucleotide polymorphisms in drug metabolism, and the inadequate resilience of the patient’s immune system can all potentially contribute to the resistance of HCC patients to TKIs ( Chen et al, 2022 ; Salani et al, 2022 ). Therefore, in-depth research on drug resistance mechanisms is essential for understanding the emergence of drug resistance in HCC cells.…”

Evolving Landscape in Liver Transplantation for Hepatocellular Carcinoma: From Stage Migration to Immunotherapy Revolution

“…ICIs have revolutionized the management of HCC after TKIs; however, single-agent ICIs, such as nivolumab, pembrolizumab and tislelizumab, reported an ORR of less than 20% due to primary resistance mechanisms against these strategies [32][33][34][35]. Combination therapies of anti-PD-1 and anti-angiogenic and anti-PD-1 and anti-CTLA4 exhibit a more promising anti-tumor efficacy.…”

The improving strategies and applications of nanotechnology-based drugs in hepatocellular carcinoma treatment

“…Tumor immunotherapy includes the use of cancer vaccines, cell therapy, immune checkpoint inhibitors, monoclonal antibodies, and small molecule inhibitors ( Llovet et al, 2022 ). However, some patients with tumor immunotherapy show no response after achieving significant results in a short period, which is attributed to immune system resistance ( Salani et al, 2022 ). For example, the surface of tumor cells expresses the programmed cell death protein 1 ligand (PD-L1), which can cause the function of cytotoxic T cells to be inhibited.…”