Quantifying Systemic Immunosuppression to Personalize Cancer Therapy

Study Overview
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Brief Summary
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The Serpentine (Stratify cancER PatiENTs by ImmuNosupprEssion) project, represents the most consistent effort so far attempted to translate MDSC into clinical practise by producing an off-the-shelf compliant assay for quantifying these cells in peripheral blood.

Detailed Description
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The study will demonstrate that this assay helps personalizing cancer therapies by tailoring them to immune patient features. The project will also take advantage of innovative and high-throughput techniques to define additional MDSC related biomarkers and, most importantly, to identify novel drugs for Myeloid-derived Suppressor Cells (MDSC) blocking in predisposed patients. Finally,it will perform the first survey assessing the link between MDSC and perceived social isolation, an emerging western social problem recently shown to cause myeloid cell dysfunction and immunosuppression though neuroendocrine circuits. Globally, the Serpentine proposal has the ambitious goal to translate into the clinical oncological practise the use of MDSC quantification as a tool for the systematic assessment of systemic immunosuppression, providing at the same time operational insights into the strategies to overcome this pillar mechanism of cancer progression.

Official Title
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Quantifying Systemic Immunosuppression to Personalize Cancer Therapy

Conditions
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Melanoma, Breast Cancer, Renal Cell Carcinoma, Urinary Bladder Cancer, Squamous Cell Carcinoma of Head and Neck, Small Cell Carcinoma, NSCLC

Intervention / Treatment
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* Other: MDSC quantification


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Histologically documented diagnosis of metastatic/locally advanced melanoma, hormone-refractory breast cancer, RCC and UC, SCCHN, SCC or NSCLC, stage III resectable NSCLC will also be included Will and ability to comply with the protocol Willingness and ability to provide an adequate archival Formalin-Fixed Paraffin-Embedded (FFPE) tumor sample available for exploratory biomarker analysis Age from 18 to 90 years at the time of recruitment ECOG Performance Status <= 2 Understanding and signature of the informed consent Consenting to participate to the socio-economical-psychological survey Exclusion Criteria Known history of HIV infection Serious neurological or psychiatric disorders Pregnancy or lactation Inability or unwillingness of participant to give written informed consent Inability or unwillingness to be regularly followed up at the same center

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Metastatic melanoma patients<br>MDSC quantification in Metastatic melanoma patients undergoing first/second-line treatment with BRAF and MEK inhibitors (BRAFi+MEKi) or immune checkpoint inhibitors (antagonists of PD-1 or CTL4, or both) (n=100); | Other: MDSC quantification<br>* Blood sample will be collected at baseline and during therapy, and, optionally, in case of disease progression (PD).<br>|
| hormone receptor positive/Human Epidermal growth factor Receptor-2 negative cancer patients<br>MDSC quantification in Metastatic HR+(hormone receptor positive)/ HER2-(Human Epidermal growth factor Receptor-2 negative) breast cancer patients already treated with a combination of an hormonal agent and a CDK(Cyclin-dependent kinase)4/6 inhibitor and receiving chemotherapy (n=100); | Other: MDSC quantification<br>* Blood sample will be collected at baseline and during therapy, and, optionally, in case of disease progression (PD).<br>|
| Advanced RCC(renal cell carcinoma) patients<br>MDSC quantification Advanced RCC patients receiving immune checkpoint inhibitors (antagonists of PD-1, PD-L1 or CTL4, or combinations) or anti-angiogenics alone or combined with immune checkpoint inhibitors; locally advanced/metastatic UC(Urothelial Carcinoma) patients receiving first-line chemotherapy, immune checkpoint inhibitors or combinations (n=100); | Other: MDSC quantification<br>* Blood sample will be collected at baseline and during therapy, and, optionally, in case of disease progression (PD).<br>|
| SCCHN or SCC(Small Cell Carcinoma) patients<br>MDSC quantification in SCCHN or SCC(Small Cell Carcinoma) patients treated with first-line chemotherapy, cetuximab,immune checkpoint inhibitors or combinations (n=100). | Other: MDSC quantification<br>* Blood sample will be collected at baseline and during therapy, and, optionally, in case of disease progression (PD).<br>|
| NSCLC patients<br>MDSC quantification in NSCLC patients undergoing radical surgery for stage III cancer (n=100);patients with unresectable/metastatic NSCLC receiving first line treatment with chemotherapy, immune checkpoint inhibitors (antagonists of PD-1, PD-L1 or CTL4) or combinations (n=100). | Other: MDSC quantification<br>* Blood sample will be collected at baseline and during therapy, and, optionally, in case of disease progression (PD).<br>|
| Age and gender-matched healthy donors<br>Age and gender-matched healthy donors (n=400) will be enrolled in the study, to allow us investigating the same immunological parameters under physiological conditions and define normal values for the myeloid-related biomarkers here assessed. | Other: MDSC quantification<br>* Blood sample will be collected at baseline and during therapy, and, optionally, in case of disease progression (PD).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunological endpoint | Frequency, in terms of percentage and absolute count of the defined cell subsets in whole blood and stored PBMC | baseline, that is prior to start the therapy (Visit_1) | 
| Immunological endpoint | Frequency, in terms of percentage and absolute count of the defined cell subsets in whole blood and stored PBMC | around one month/before the time-corresponding treatment cycle (Visit_2) | 
| Immunological endpoint | Frequency, in terms of percentage and absolute count of the defined cell subsets in whole blood and stored PBMC | around three months/before the time-corresponding treatment cycle (Visit_3) | 
| Immunological endpoint | Frequency, in terms of percentage and absolute count of the defined cell subsets in whole blood and stored PBMC | Through study completion, an average of 2 year | 
| Clinical endpoint_PFS | Progression-Free Survival (PFS) | Through study completion, an average of 2 year | 
| Clinical endpoint_OS | Overall Survival (OS) | Through study completion, an average of 2 year | 
| Clinical endpoint_ORR | Overall Response Rate (ORR) | Through study completion, an average of 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myeloid Index Score (MIS) | Myeloid Index Score (MIS)=0 vs MIS>0 or higher values | Through study completion, an average of 2 year | 
| Index score values | Index score values on plasma cytokine concentration or MDSC-miRs | Through study completion, an average of 2 year | 
| Transcriptional signatures_PBMC | Transcriptional signatures identified on PBMC and sorted myeloid cells form whole blood | baseline, that is prior to start the therapy (Visit_1) or at the first disease evaluation (around after three months) | 
| Transcriptional signatures_myeloid cells | Transcriptional signatures identified on sorted myeloid cells form whole blood | baseline, that is prior to start the therapy (Visit_1) or at the first disease evaluation (around after three months) | 
| Phospho-kinome signature result | Phospho-kinome signature as assessed by Cytof analysis in stored PBMC | Through study completion, an average of 2 year | 
| Metabolomic profiles | The concentration of individual metabolites or cluster of metabolites implicated in amino acid and lipid metabolism | Through study completion, an average of 2 year | 
| Socio-Economical-Psychological (SEP) score | Socioeconomic and psychological (perceived social isolation) score, calculated through a dedicated questionnaire | Through study completion, an average of 2 year |