Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcγ receptors on immune cells. Although SNPs in genes encoding Fcγ 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 FcγR status and cetuximab-mediated ADCC. Patients carrying the FcγRIIa H alleles 131H/H and 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P = 0.013). Patients carrying FcγRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P = 0.001). Progression-free survival of patients with an FcγRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P = 0.05), whereas no significant difference was observed for overall survival. Twenty-eight 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 FcγR polymorphisms and predicted cetuximab responsiveness. Cancer Immunol Res; 4(4); 366–74. ©2016 AACR.

Background: Anti-EGFR monoclonal antibodies have shown efficacy in the treatment of metastatic colorectal cancer (mCRC). One of the mechanism is the antibody-dependent cell-mediated cytotoxicity (ADCC) in which Fc region of the antibody binds to the Fc gamma receptors (FcγR) expressed by immune cells. The present study investigated the association between single nucleotide polymorphisms of FcγRIIa and FcγRIIIa and clinical outcome in mCRC treated with anti-EGFR antibodies. Methods: Seventy-four consecutive patients with mCRC were analyzed. The genotypes for FcγRIIa-131 histidine (H)/arginine (R), FcγRIIIa-158 valine (V)/phenylanaline (F) polymorphisms were evaluated by directly sequencing. Multiplex allele-specific polymerase chain reaction was performed for FcγRIIIa-158 valine (V)/phenylanaline (F). Correlations between FcγR polymorphisms, baseline patient and tumor features were studied by contingency tables and the chi-square test. The Kaplan-Meier product limit method was applied to the progression-free survival (PFS) curves. Univariate analysis was performed with the log-rank test. Cox proportional-hazards regression was used to analyze the effect of multiple risk factors on PFS. Results: FcγRIIIa polymorphisms were significantly associated with response to anti-EGFR-based therapy in 49 patients with kras wt tumors (p=0.035). There was not association with response for FcγRIIa polymorphisms. Furthermore, obtained results suggested that prognosis is particularly unfavorable for patients carrying the FcγRIIIa-158F/F genotype (median PFS V/V, V/F, F/F: 18.2 vs 17.3 vs 9.4 months). No prognostic ability was identified for FcγRIIa polymorphisms. Conclusions: In mCRC patients the presence of FcγRIIIa-F can predict resistance to anti-EGFR therapy and unfavorable prognosis.

Dendritic cell (DC) cancer vaccines are a promising therapeutic approach, leveraging the immune system to fight tumors. These vaccines utilize DCs’ ability to present tumor-associated antigens to T cells, triggering a robust immune response. DC vaccine development has progressed through three generations. The first generation involved priming DCs with tumor-associated antigens or messenger RNA outside the body, showing limited clinical success. The second generation improved efficacy by using cytokine mixtures and specialized DC subsets to enhance immunogenicity. The third generation used blood-derived DCs to elicit a stronger immune response. Clinical trials indicate that cancer vaccines have lower toxicity than traditional cytotoxic treatments. However, achieving significant clinical responses with DC immunotherapy remains challenging. Combining DC vaccines with immune checkpoint inhibitors (ICIs), such as anticytotoxic T-lymphocyte Antigen 4 and antiprogrammed death-1 antibodies, has shown promise by enhancing T-cell responses and improving clinical outcomes. These combinations can transform non-inflamed tumors into inflamed ones, boosting ICIs’ efficacy. Current research is exploring new checkpoint targets like LAG-3, TIM-3, and TIGIT, considering their potential with DC vaccines. Additionally, engineering T cells with chimeric antigen receptors or T-cell receptors could further augment the antitumor response. This comprehensive strategy aims to enhance cancer immunotherapy, focusing on increased efficacy and improved patient survival rates.

Dendritic cells (DCs) are acknowledged as the most potent professional antigen-presenting cells (APCs), able to induce adaptive immunity and support the innate immune response

Background: PD-1 blocking agents, such as nivolumab, have demonstrated clear anti-tumor effects and clinical benefits in a subset of patients with advanced malignancies. Nonetheless, more efforts are needed to identify reliable biomarkers for outcome, to correctly select patients who will benefit from anti-PD-1 treatment. The aim of this study was to investigate the role of peripheral CD8+T cells expressing CD73, involved in the generation of the immune suppressive molecule adenosine, in predicting outcome after nivolumab treatment in advanced melanoma patients. Methods: PBMCs from 100 melanoma patients treated with nivolumab were collected at National Cancer Institute “G. Pascale” of Naples. Frequencies of CD8+ lymphocytes phenotypes were assessed by flow cytometry at baseline before nivolumab treatment, along with clinical characteristics and blood count parameters. Healthy controls (n = 20) were also analysed. Percentages of baseline T cells expressing PD-1 and CD73 were correlated with outcome after nivolumab treatment. Results: Melanoma patients presented a lower frequency of total circulating CD8+ lymphocytes than control subjects (p = 0.008). Patients with low baseline percentage of circulating CD8+PD-1+CD73+ lymphocytes (< 2.3%) had better survival (22.4 months vs 6.9 months, p = 0.001). Patients (39%) with clinical benefit from nivolumab therapy presented a significantly lower frequency of circulating CD8+PD-1+CD73+ lymphocytes than patients who progressed to nivolumab treatment (p = 0.02). Conclusions: Our observations suggest that baseline CD73 expression on circulating CD8+PD-1+ lymphocytes appear a promising biomarker of response to anti-PD-1 treatment in melanoma patients. Further investigations are needed for validation and for clarifying its role as prognostic or predictive marker.