Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy

Abstract

Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcg receptors on immune cells. Although SNPs in genes encoding Fcg receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer, a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic colorectal cancer (mCRC) patients at diagnosis in a study that assessed FcgR status and cetuximab-mediated ADCC. Patients carrying the FcgRIIa H alleles 131H/H and 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P ¼ 0.013). Patients carrying FcgRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P ¼ 0.001). Progression-free survival of patients with an FcgRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P ¼ 0.05), whereas no significant difference was observed for overall survival. Twentyeight of 50 mCRC patients with wild-type KRAS received cetuximab. The average ADCC-mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response, 21% in patients with stable disease and 9% in patients with progressive disease. To characterize basal natural killer (NK) activity, cytotoxicity was evaluated in 39 of 96 mCRC patients. Patients who responded to first-line treatment had higher NK-cell cytotoxicity. Thus, although limited to this cohort of patients, in vitro cetuximab-mediated ADCC correlated with FcgR polymorphisms and predicted cetuximab responsiveness.

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

“…The efficacy of mAb treatment, including that of Cetuximab, is influenced by FCγR polymorphism (184). The homozygous genotype of valine at position 158 on the FcγRIIIa receptor (158 V/V genotypes), as opposed to the 158 V/F or 158 F/F FcγRIIIa genotypes is often, but not always, associated with improved clinical outcomes (185)(186)(187)(188)(189). Moreover, FCγ receptor affinity is impacted by patterns of antibody glycosylation (190) and by particular IgG variants.…”

Effectiveness of Antibody-Drug Conjugate (ADC): Results of In Vitro and In Vivo Studies

“…In the present study, the in vivo and in vitro experiments confirmed that the antibody portion of an ADC drug (Cetuximab) served as a vector for the effector molecule (tubulin inhibitor MMAE) to bring MMAE to the targeted tumor tissue. The small molecule cytotoxic cytokines play use high cytotoxicity to kill local cells, while monoclonal antibodies can also maintain their own antibody-dependent cytotoxicity (ADCC) or Fc-mediated complement-dependent cytotoxicity (CDC) to exert their own effects [ 15 ]. This method combines their strengths and complements their weaknesses, and they can exert a strong anti-tumor effect, reduce damage to normal tissues and cells, and also the antibody resistance problem [ 16 ].…”

Natural killer cells activity in a metastatic colorectal cancer patient with complete and long lasting response to therapy

“…Interestingly, we previously reported that patients affected by mCRC with high NK-cell cytotoxicity, independently from the type of therapy, showed a significantly higher response rate and a longer progression-free survival (PFS) compared with patients with low NK-cell cytotoxicity[ 9 ]. Due to the complex and dynamic nature of the immune system we are evaluating the hypothesis that decrease over time of NK cell activity could associate with progression of the tumor.…”

“…The issue is very complex since the interactions between components of the immune system and tumor cells are largely unknown. We recently reported that polymorphisms of receptors involved in ADCC (antibody-mediated cellular cytotoxicity) as well as the NK cells activity of patients affected by mCRC were predictive and prognostic[ 9 ]. Additionally, MDSCs (myeloid-derived suppressor cells) and Tregs (regulatory T-cell) are a component of the immune system that may promote tumor progression[ 10 ] by inhibiting both innate and adaptive immune responses.…”