A multiparametric approach based on circulating biomarkers to monitor response and immune-related adverse reactions to immunotherapy of cancer.
ProjectImmune-checkpoint inhibitors (ICIs) restore anti-tumor immune responses by T cells. Most attention has been directed towards identifying predictive biomarkers; although predictive accuracy has been validated for expression of PD-L1 on tumor and infiltrating immune cells, much of the immunological compartment is left out of tumor biopsy–based analyses. Therefore, an early response indicator, such as a biomarker of immune activation or reduction of a tumor-specific mutant allele that can be monitored in plasma by liquid biopsy, is much needed since it would generate information in a clinically actionable time frame that could help guide treatment decisions.
Moreover, ICIs may cause immune-related adverse events (irAEs), which impact on a patient's quality of life and may require the use of immunosuppressive treatments. We lack predictors of such toxicities, that would instead be critical for a tailored approach. Having considered all these facts, ideally, therapy decisions would be made on the basis of patient-specific immunological biomarkers.
In our proposal, we aim at building a comprehensive set of biomarkers, made up of immunological, molecular and cytofluorimetric data on biological samples (liquid biopsy and tissues). The identification and validation of this tool will allow us to stratify subgroups of patients with different responses to ICIs and risk of irAEs. In particular, we will enroll patients affected by unresectable non-small cell lung cancer (NSCLC) and skin cancer, including advanced Merkel cell carcinoma (MCC), melanoma, cutaneous squamous cell carcinoma (CSCC) and candidate to treatment with anti-PD-1 agents (i.e., pembrolizumab) alone or in combination with chemotherapy.
Blood samples will be obtained at baseline (before the start of treatment) and at regular time intervals during treatment (at each visit of re- evaluation) and follow-up until disease progression. Blood will be processed for extraction of circulating tumor DNA (ctDNA) and its analysis by next generation sequencing (NGS) to identify mutant alleles released by tumor in the blood; their variation will be considered a biomarker of response or progression to treatment. In addition to this, blood will be processed to obtain serum for the measurement of cytokines (IFN-, TNF-, TGF-ß, IL-2, -4, -6, -10, -12, -17, and -22) by ELISA to correlate their changes with tumor response and, in particular, irAEs. In addition to this, cell population subtypes will be investigated, including: absolute lymphocyte and neutrophil counts, neutrophil/lymphocyte ratio, helper and effector T cells, regulatory T cells, naïve/memory T lymphocytes, myeloid-derived suppressor cells, plasmacytoid dendritic cells, dim and bright NK cells, NKT cells, myeloid dendritic cells, monocytes subsets, TAMs and B lymphocytes. Finally, all irAEs will be carefully collected and correlated with the type of treatment delivered to the patient, her/his characteristics and immunological activation.
Moreover, ICIs may cause immune-related adverse events (irAEs), which impact on a patient's quality of life and may require the use of immunosuppressive treatments. We lack predictors of such toxicities, that would instead be critical for a tailored approach. Having considered all these facts, ideally, therapy decisions would be made on the basis of patient-specific immunological biomarkers.
In our proposal, we aim at building a comprehensive set of biomarkers, made up of immunological, molecular and cytofluorimetric data on biological samples (liquid biopsy and tissues). The identification and validation of this tool will allow us to stratify subgroups of patients with different responses to ICIs and risk of irAEs. In particular, we will enroll patients affected by unresectable non-small cell lung cancer (NSCLC) and skin cancer, including advanced Merkel cell carcinoma (MCC), melanoma, cutaneous squamous cell carcinoma (CSCC) and candidate to treatment with anti-PD-1 agents (i.e., pembrolizumab) alone or in combination with chemotherapy.
Blood samples will be obtained at baseline (before the start of treatment) and at regular time intervals during treatment (at each visit of re- evaluation) and follow-up until disease progression. Blood will be processed for extraction of circulating tumor DNA (ctDNA) and its analysis by next generation sequencing (NGS) to identify mutant alleles released by tumor in the blood; their variation will be considered a biomarker of response or progression to treatment. In addition to this, blood will be processed to obtain serum for the measurement of cytokines (IFN-, TNF-, TGF-ß, IL-2, -4, -6, -10, -12, -17, and -22) by ELISA to correlate their changes with tumor response and, in particular, irAEs. In addition to this, cell population subtypes will be investigated, including: absolute lymphocyte and neutrophil counts, neutrophil/lymphocyte ratio, helper and effector T cells, regulatory T cells, naïve/memory T lymphocytes, myeloid-derived suppressor cells, plasmacytoid dendritic cells, dim and bright NK cells, NKT cells, myeloid dendritic cells, monocytes subsets, TAMs and B lymphocytes. Finally, all irAEs will be carefully collected and correlated with the type of treatment delivered to the patient, her/his characteristics and immunological activation.