Heterogeneity of Response and Immune System Activity during Treatment with Nivolumab in Hepatocellular Carcinoma: Results from a Single-Institution Retrospective Analysis

Abstract

Treatment of hepatocellular carcinoma (HCC) is rapidly evolving, with many new therapeutic options; in particular, immunotherapy (IT) is acquiring a major role, even in combination regimens. Despite these promising results, an important limitation is the lack of prognostic and predictive factors that prevent provision of a tool for patient stratification in order to select the most appropriate strategy. Furthermore, response assessment can be challenging with IT due to peculiar patterns such as mixed responses or pseudoprogression. We analyzed biological and clinical features from the first 10 HCC patients treated with nivolumab in our institution. Analysis of patterns of response in CT assessment revealed complete response in pulmonary lesions, along with heterogeneous behavior in the liver and other organ lesions. Peripheral blood mononuclear cells (PBMC) analysis in the first four patients showed unique alterations in a patient with poor prognosis, both at baseline (lower percentage of effector T cells, higher percentage of natural killer T [NK/T] cells) and during treatment with nivolumab (decrease in nonclassical monocytes, increase in monocytic myeloid-derived suppressor cells [MO-MDSC]), suggesting a possible prognostic role for these features. Although obtained in a small cohort of patients, our results open a new perspective for understanding mechanisms underlying IT outcomes in HCC patients.

Efficacy of lenvatinib plus pembrolizumab in hepatocellular carcinoma with metachronous lung metastasis: a report of two cases

“…Organ-specific ORRs for liver, lung, lymph node, and other metastases were 10.1%, 24.3%, 37.14%, and 14.6%, respectively. 6 Rapposelli et al 7 reported different response pattern based on the site of the lesion among 10 patients with HCC treated with nivolumab. CR was observed in two pulmonary lesions (100%) and heterogeneous response in the liver (2 CR, 20 SD, 9 PD; 6%, 65%, 29%, respectively) (RECIST) and other organ lesions (2 PR, 1 SD, 5 PD; 25%, 12.5%, 62.5%, respectively).…”

“…8 Liver lesions in HCC are associated with an immunosuppressive microenvironment. 7 T-cell exhaustion, immune dysfunction, and high levels of immunosuppressive molecules comprise the immunosuppressive features of the liver microenvironment. In patients with melanoma and NSCLC, liver metastases characterized by reduced CD8+ T-cell infiltration further show the immunosuppressive microenvironment of the liver.…”

Unraveling the Complexities of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

“…PsP can occur not only in existing target lesions but also in new lesions. For instance, Rapposelli et al 123 observed PsP in bone metastasis (rather than the primary lesions) in a patient with HCC. Similarly, Sangro et al 117 reported the growth of nontarget lesions (tumors in the lung, left iliac crest, and pelvic lymph nodes) in HCC patients following therapy with atezolizumab plus bevacizumab, as assessed by computed tomography (CT).…”

Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook

“…A handful of biomarkers are currently identified to be associated with an improved survival and response in nivolumab treatment, such as PD-1 and PD-L1 expression, 141 , 149 a good AFP response, 150 inflammatory cytokines (CD3 and CD8) 149 and peripheral blood mononuclear cells (effector T cells and nonclassical monocytes). 151 This algorithm remains yet to be confirmed in some large prospective studies.…”