Abstract
BackgroundImmunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. Here, we illustrate the use of a causal inference model to identify predictive biomarkers of CIMAvaxEGF success in the treatment of Non–Small Cell Lung Cancer Patients.MethodsData from a controlled clinical trial evaluating the effect of CIMAvax-EGF were analyzed retrospectively, following a causal inference approach. Pre-treatment potential predictive biomarkers included basal serum EGF concentration, peripheral blood parameters and immunosenescence biomarkers. The proportion of CD8 + CD28- T cells, CD4+ and CD8+ T cells, CD4/CD8 ratio and CD19+ B cells. The 33 patients with complete information were included. The predictive causal information (PCI) was calculated for all possible models. The model with a minimum number of predictors, but with high prediction accuracy (PCI > 0.7) was selected. Good, rare and poor responder patients were identified using the predictive probability of treatment success.ResultsThe mean of PCI increased from 0.486, when only one predictor is considered, to 0.98 using the multivariate approach with all predictors. The model considering the proportion of CD4+ T cell, basal Epidermal Growth Factor (EGF) concentration, neutrophil to lymphocyte ratio, Monocytes, and Neutrophils as predictors were selected (PCI > 0.74). Patients predicted as good responders according to the pre-treatment biomarkers values treated with CIMAvax-EGF had a significant higher observed survival compared with the control group (p = 0.03). No difference was observed for bad responders.ConclusionsPeripheral blood parameters and immunosenescence biomarkers together with basal EGF concentration in serum resulted in good predictors of the CIMAvax-EGF success in advanced NSCLC. Future research should explore molecular and genetic profile as biomarkers for CIMAvax-EGF and it combination with immune-checkpoint inhibitors. The study illustrates the application of a new methodology, based on causal inference, to evaluate multivariate pre-treatment predictors. The multivariate approach allows realistic predictions of the clinical benefit of patients and should be introduced in daily clinical practice.
Highlights
Immunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy
Immunosenescence markers as the proportion of CD8 + CD28− cells, CD4 cells, and the CD4/CD8 ratio after first-line chemotherapy were associated with CIMAvax-Epidermal Growth Factor (EGF) clinical benefit
We selected all patients with measures of pre-treatment basal EGF concentration, peripheral blood parameters, inflammation, and immunosenescence biomarkers
Summary
Immunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. CIMAvax-EGF is a therapeutic anticancer vaccine, developed in Cuba under the concept that inducing Epidermal Growth Factor (EGF) deprivation, which involves manipulating an individual’s immune response to release its effector antibodies against EGF, tumour size or its progression, can be reduced. Immunosenescence markers as the proportion of CD8 + CD28− cells, CD4 cells, and the CD4/CD8 ratio after first-line chemotherapy were associated with CIMAvax-EGF clinical benefit. All these studies point to the importance given to the search of predictive biomarkers that allow the selection of patients who can receive a real benefit with the vaccine
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