Serum Concentration of CD137 and Tumor Infiltration by M1 Macrophages Predict the Response to Sintilimab plus Bevacizumab Biosimilar in Advanced Hepatocellular Carcinoma Patients

Abstract

Purpose: This study aimed to investigate the biomarkers of sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar) in advanced HCC, as well as their safety and efficacy. Experimental Design: A total of 50 patients with advanced HCC received sintilimab (200 mg) plus IBI305 (7.5 or 15 mg/kg), treated every 3 weeks in a phase 1b clinical study. We performed baseline serum cytokine analysis using bead-based multiplex immunoassay and multiplex immunofluorescence on tissue specimens to discover novel biomarkers of response to VEGF/PD-1 combination therapy in HCC. Results: The overall response rate was 34.0% (17/50). The median progression-free survival (PFS) and the median overall survival were 10.5 and 20.2 months, respectively. The incidence of grade 3-5 adverse events was lower in the 7.5 mg/kg (13.8%) than in the 15 mg/kg (28.6%) dose groups. Biomarker analysis showed that the serum CD137 concentration was significantly higher in patients with clinical benefit (CB) than in those without CB (median, 32.8 vs 19.8 pg/mL, P = 0.034). A markedly longer PFS was observed in patients with high CD137 concentrations compared to those with low concentrations (median, 14.2 vs 4.1 months, P = 0.001). The higher density of M1 macrophages (CD68+CD163-) in the stroma was also associated with higher efficacy (P = 0.033) and a longer PFS (P = 0.024). Conclusion: Sintilimab plus IBI305 was well tolerated and was effective therapy for advanced HCC. Both serum concentrations of CD137 and tumor infiltration of M1 macrophages may serve as potential predictive biomarkers.

Tumor microenvironment features decipher the outperformance of neoadjuvant immunochemotherapy over chemotherapy in resectable non-small cell lung cancer

“…Surgical tissue specimens were subjected to the examination of the TIME, which was performed as previously described by 3D Medicines, Inc., a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory ( 16 ). The Akoya OPAL Polaris 7-Color Automation IHC kit (NEL871001KT) was applied to conduct multiplex immunofluorescence (mIF) staining following manufacturer’s instructions.…”

Case report: Primary hepatocellular carcinoma with portal vein tumor thrombus characterized by active tumor immune microenvironment achieving a complete response following treatment of combined immunotherapy

“…Besides cytotoxic T cells, other immune cell subsets may also contribute to anti-tumor immunity, such as tumor-associated macrophages (TAMs) and NK cells. TAMs can be divided into different phenotypes, including M1 macrophages and M2 macrophages ( 13 ). In a phase 1b study of sintilimab (a PD-1 inhibitor) plus a bevacizumab biosimilar in advanced HCC, the high infiltration of M1 macrophages (≥118.1 cells/mm 2 ) were found to be significantly correlated with a better clinical benefit and prolonged survival ( 13 ).…”

“…TAMs can be divided into different phenotypes, including M1 macrophages and M2 macrophages ( 13 ). In a phase 1b study of sintilimab (a PD-1 inhibitor) plus a bevacizumab biosimilar in advanced HCC, the high infiltration of M1 macrophages (≥118.1 cells/mm 2 ) were found to be significantly correlated with a better clinical benefit and prolonged survival ( 13 ). Of note, we observed the presence of TLS, which is lymphoid-like aggregates forming in non-lymphoid tissues during chronic inflammation and tumor progression.…”

Tumor‐associated macrophages in liver cancer: From mechanisms to therapy

“…PI3Kδ/γ inhibition is an effective ther-apeutic strategy for Hodgkin lymphoma [78]. The higher the CD137 level in the serum and the higher the M1 density in the matrix in 50 patients with advanced HCC who received sintilimab (anti-PD-1) plus IBI305 (a bevacizumab biosimilar), the longer the median progression-free survival and median overall survival [24]. β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor MK-8931 potently reprogramed M2 TAMs into M1 TAMs via inhibiting IL-6-STAT3 signaling and activated macrophage phagocytosis in cancer cells [79].…”

“…Combination therapy is the primary treatment strategy for liver cancer [21]. We explored studies on combined therapy with multi-target inhibitors such as sorafenib or lenvatinib and evaluated the efficacy of immune checkpoint inhibitors (ICIs) such as anti-programmed cell death protein 1 (PD-1) [22][23][24]. A critical hypothesis is whether macrophage metabolism disorder is the core resistance mechanism to such drugs.…”