Results of a study recently published in the journal JCO Precision Oncology show that in the clinical trial context, combined analysis of the inflammatory status of the tumor microenvironment classified by the VIGex gene expression signature and circulating tumor DNA (ctDNA) by liquid biopsy may improve response prediction to immunotherapy in patients with advanced solid tumors.

Immunotherapy is a type of cancer treatment that boosts the immune system to fight cancer by helping it to recognize and attack tumor cells. While this therapeutic strategy continues to revolutionize the treatment of an increasing number of tumor types, only a small fraction of biomarker-selected patients will benefit from immunotherapy.

“Cancer immunotherapy fails to achieve clinical responses in all patients and does not yield benefit in the treatment of many tumor types. There is therefore an unmet clinical need to identify robust biomarkers predictive of response to immune-based treatments,” said Elena Garralda, Medical. Oncologist at the Vall d’Hebron University Hospital (HUVH), Director of VHIO’s UITM-CaixaResearch, and a co-author of this present study.

“In this context, immune gene expression signatures are emerging as potential biomarkers of response for immunotherapy. At VHIO, we have developed the VIGex gene expression signature as a predictive tool to help guide patient selection for immunotherapy,” observed Ana Vivancos, Head of VHIO’s Cancer Genomics Group and a co-author of this study.

VIGex is an immune gene signature based on the expression level of 12 key genes implicated in adaptive immune responses that has been developed in both Nanostring and RNA sequencing platforms and analytically validated in Vivancos’ laboratory and at the Princess Margaret Cancer Center in Toronto. This novel tool classifies tumor samples into three categories based on the inflammatory status of the tumor microenvironment: hot, intermediate-cold (I-Cold) and cold subgroups. VIGex-Hot has been associated with better immunotherapy outcomes.

Combined VIGex and liquid biopsy analysis

This present study is the result of an international collaboration between investigators at VHIO and colleagues at the Princess Margaret Cancer Center including Philippe Bedard, Clinical Director of Cancer Genomics, and Lillian Siu, Medical Oncologist and Director of its Phase I Program.

The researchers analyzed the performance of VIGex and other biomarkers of response to immunotherapy in an independent data set of patients treated with pembrolizumab in the INSPIRE phase II clinical trial which was conducted at the Princess Margaret Cancer Center and directed by Lillian Siu. Findings show that the VIGex-Hot subgroup was associated with higher overall survival and progression-free survival.

“We investigated the combined performance of ctDNA changes and other biomarkers including tumor mutational burden, PD-L1 expression using immunohistochemistry, and levels of ctDNA by liquid biopsy. We have found that the use of VIGex categorization of tumor samples pre-treatment and analysis of changes in ctDNA dynamics detected by liquid biopsy improves prediction of response to immunotherapy,” said Alberto Hernando-Calvo, Medical Oncologist at Vall d’Hebron, Core Phase 1 Investigator of VHIO’s UITM-CaixaResearch, and first author of this study.

“If a patient’s tumor sample pre-treatment with immunotherapy was classified as VIGex-Hot and a decrease in the quantity of ctDNA in plasma was observed during the first two treatment cycles compared with baseline, this associated with greater clinical benefit,” added Hernando- Calvo, who is also an investigator of VHIO’s Cancer Genomics Group.

Next steps to biometric validation

“While our findings provide proof-of-principle for the combined use of VIGex classification and ctDNA dynamics to improve immunotherapy response prediction, these results are retrospective. Future prospective studies are required to establish the clinical utility of this approach for patient selection and guiding tailored immunotherapy treatment decisions,” said Hernando-Calvo.

A Phase III clinical trial led by Irene Braña, Head of VHIO’s Head and Neck Cancer Group, has been designed to assess the efficacy of immunotherapy plus radiotherapy in patients with squamous cell carcinoma of the head and neck. As part of this study, the use of VIGex and ctDNA dynamics by liquid biopsy will be evaluated to prospectively establish the clinical utility of this predictive biomarker combination for patient selection or treatment de-escalation strategies.