Search

Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1-5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6,7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Background and Aims: Combination atezolizumab/bevacizumab is the gold standard for first‐line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. Methods: 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression‐free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment‐related adverse events (trAEs) were evaluated. Results: The elderly (n = 116) had higher rates of non‐alcoholic fatty liver disease (19.8% vs. 2.7%; p <.001), presenting with smaller tumours (6.2 cm vs 7.9 cm, p =.02) with less portal vein thrombosis (31.9 vs. 54.7%, p =.002), with fewer patients presenting with BCLC‐C stage disease (50.9 vs. 74.3%, p =.002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65–2.02 p =.63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54–1.92; p =.72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p =.27) and DCR (77.5% vs. 66.1%; p =.11) compared to younger patients. Atezolizumab‐related (40.5% vs. 48.0%; p =.31) and bevacizumab‐related (44.8% vs. 41.3%; p =.63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity‐related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients. Conclusions: Atezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab + bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase II study is the first trial to evaluate the safety and efficacy of atezolizumab + bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life. Clinical Trial Registration: NCT04224636 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]