Evaluation of antibody-dependent cell-mediatedcy totoxicity activity and cetuximab response in KRAS wildtype metastatic colorectal cancer patients

AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.

Circulating cytokines and outcome in metastatic colorectal cancer patients treated with regorafenib

BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy.AIM To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib.METHODS Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers.The proteins evaluated(TNF-α,TGF-β,VEGF,CCL-2,CCL-4,and CCL-5)were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis.RESULTS We found that TNF-αbasal level was significantly higher in mCRC patients compared to healthy individuals.Non Responder(NR)patients showing progression of disease(n=12)had higher basal level of TGF-β,TNF-α,VEGF,CCL-2 and CCL-5 compared to Responder(R)patients(complete response CR,n=1;partial response PR,n=1;Stable Disease SD,n=3).On the contrary,plasma basal level of CCL-4 was higher in R compared to NR patients.High values of TGF-βand TNF-αnegatively correlated with progression free survival.CONCLUSION These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.