Background: Oncolytic viruses represent a novel form of cancer immunotherapy. Vaccinia viruses encoding humanT cell co-stimulatory molecules have demonstrated clinical activity in phase I clinical trials in patients with advancedmelanoma. However, predictive biomarkers of therapeutic response have not yet been identified.Methods: A customized microarray was performed to identify changes in peripheral blood mononuclear cell(PBMC) gene expression upon exposure to recombinant oncolytic vaccinia viruses. Up-regulated and downregulatedgenes were identified and selected for further analysis using PBMC samples from normal donors andoncolytic virus-treated patients before and after viral injection. Quantitative PCR and flow cytometry of defined T cellsubsets was performed to evaluate expression patterns and clinical correlations.Results: The microarray identified 301 genes that were up-regulated and 960 genes that were down-regulated in Tcells after exposure to oncolytic vaccinia virus. The B7.1 gene was highly up-regulated and the immunoglobulin-liketranscript 2 (ILT2) gene was highly down-regulated by vaccinia-B7.1, which was consistent with the known inverseregulation of these two genes. We observed an inverse association between ILT2 expression in the tumor microenvironmentand clinical response and further identified ILT2 as a marker of regulatory CD4+ and suppressor CD8+T cell responses and whose down-regulation was predictive of therapeutic responses in patients treated with oncolyticvirus immunotherapy.Conclusions: ILT2 is a new putative biomarker of T cell and clinical response in patients treated with oncolyticvaccinia virus immunotherapy. Further confirmation of ILT2 as a biomarker requires prospective validation in alarger series of clinical trials.
Immunoglobulin-like transcript 2 (ILT2) is a biomarker of therapeutic response to oncolytic immunotherapy with vaccinia viruses
MONSURRO', Vladia;
2014-01-01
Abstract
Background: Oncolytic viruses represent a novel form of cancer immunotherapy. Vaccinia viruses encoding humanT cell co-stimulatory molecules have demonstrated clinical activity in phase I clinical trials in patients with advancedmelanoma. However, predictive biomarkers of therapeutic response have not yet been identified.Methods: A customized microarray was performed to identify changes in peripheral blood mononuclear cell(PBMC) gene expression upon exposure to recombinant oncolytic vaccinia viruses. Up-regulated and downregulatedgenes were identified and selected for further analysis using PBMC samples from normal donors andoncolytic virus-treated patients before and after viral injection. Quantitative PCR and flow cytometry of defined T cellsubsets was performed to evaluate expression patterns and clinical correlations.Results: The microarray identified 301 genes that were up-regulated and 960 genes that were down-regulated in Tcells after exposure to oncolytic vaccinia virus. The B7.1 gene was highly up-regulated and the immunoglobulin-liketranscript 2 (ILT2) gene was highly down-regulated by vaccinia-B7.1, which was consistent with the known inverseregulation of these two genes. We observed an inverse association between ILT2 expression in the tumor microenvironmentand clinical response and further identified ILT2 as a marker of regulatory CD4+ and suppressor CD8+T cell responses and whose down-regulation was predictive of therapeutic responses in patients treated with oncolyticvirus immunotherapy.Conclusions: ILT2 is a new putative biomarker of T cell and clinical response in patients treated with oncolyticvaccinia virus immunotherapy. Further confirmation of ILT2 as a biomarker requires prospective validation in alarger series of clinical trials.
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