Combining expression of GPC3 in tumors and CD16 on NK cells from peripheral blood to identify patients responding to codrituzumab

Abstract

BackgroundCodrituzumab, a monoclonal antibody targeting an oncofetal protein glypican-3 (GPC3) expressed on cell surface of hepatocellular carcinoma (HCC) induces antibody-dependent cellular cytotoxicity (ADCC) and inhibits tumor growth in preclinical studies. Based on this mechanism, tumor GPC3 expression and CD16 expression on NK cells, which are the effector cells of ADCC, were investigated to correlate with codrituzumab's clinical efficacy in patients with advanced HCC.ResultsJoint analyses of the two biomarkers revealed that both high levels of GPC3 and CD16 were required for patients to benefit from codrituzumab; lack of either one of them would lead to a loss of the therapeutic effect.ConclusionsThese results suggest the combination of tumor GPC3 expression and CD16 expression on NK cells from peripheral blood at baseline as a composite biomarker to select HCC patients for codrituzumab.ImpactThe conclusion warrants a future study in an HCC population with both high GPC3 expression and high levels of CD16 at baseline to establish codrituzumab's therapeutic benefit in HCC.MethodsData from a phase II clinical trial of codrituzumab were used for the analyses. GPC3 expression in baseline tumor biopsies was determined by immunohistochemistry (IHC) analysis, and baseline CD16 expression on NK cells were quantified by peripheral blood lymphocyte immunophenotyping. According to high or low expression of GPC3 and CD16, different patient subgroups were formed; for each subgroup, overall survival of patients having high codrituzumab exposure was compared to that of patients receiving placebo.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Additional antibodies potentially involving NK cell activation and ADCC as mechanism of action were reviewed by Wang et al (175). More recent reports of NK cell activating antibodies with varying combinatorial treatments are listed in Table 2, including anti-SLAMF7, Elotuzumab, for multiple myeloma (258); anticathepsin-D, F1, for Triple Negative Breast Cancer (179); anti-GD2, Dinutuximab and hu14.18K322A, for neuroblastoma (259,260); anti-PD-L1, Avelumab, for Triple Negative Breast Cancer (261); anti-CD38, Daratumumab, for multiple myeloma (262, 263); anti-GPC3, Codrituzumab, for hepatocellular carcinoma (264); and anti-CD33, BI 836858, for AML (265).…”

Glypican 3-Targeted Therapy in Hepatocellular Carcinoma

“…In the phase II trial of codrituzumab vs. placebo, median PFS was 2.6 months vs. 1.5 months, respectively, with a hazard ratio [HR] 0.97 and p = 0.87, and median OS was 8.7 months vs. 10 months, respectively, with HR 0.96 and p = 0.82 [65]. Nevertheless, sub-analysis of the results of the phase II trial and another study indicated that codrituzumab showed prognostic merit for HCC patients with a high immunogenicity related to ADCC and a high expression of GPC3 [65,66].…”

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

“…The amplified NK cell surface activating receptor CD107A was significantly up-regulated and could secrete more IFN-γ, and had highly cytotoxicity to many kinds of cancer cells in vitro and in vivo. Subsequently, Chen et al [93] explored the effects of CD16 overexpression in NK cells induced by monoclonal antibodies against the tumor embryo protein GPC3 (glypican-3) target to HCC. The results of immunohistochemistry (IHC) showed that GPC3 and CD16 could be expressed on tumor cells and NK cells of peripheral blood, respectively.…”