Quantifying Systemic Immunosuppression to Personalize Cancer Therapy

NCT05621837 | Recruiting DMC

• 1 other identifier: INT 48/21
• Study Type: observational
• Target: 1,000
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (7)

• Myeloid Index Score (MIS)

  Through study completion, an average of 2 year

• Index score values

  Through study completion, an average of 2 year

• Transcriptional signatures_PBMC

  baseline, that is prior to start the therapy (Visit_1) or at the first disease evaluation (around after three months)

• Transcriptional signatures_myeloid cells

  baseline, that is prior to start the therapy (Visit_1) or at the first disease evaluation (around after three months)

• Phospho-kinome signature result

  Through study completion, an average of 2 year

Study Arms (6)

Metastatic melanoma patients

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

hormone receptor positive/Human Epidermal growth factor Receptor-2 negative cancer patients

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

Advanced RCC(renal cell carcinoma) patients

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

SCCHN or SCC(Small Cell Carcinoma) patients

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

NSCLC patients

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

Age and gender-matched healthy donors

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

Interventions

MDSC quantification OTHER

Blood sample will be collected at baseline and during therapy, and, optionally, in case of disease progression (PD).

Advanced RCC(renal cell carcinoma) patients; Age and gender-matched healthy donors; Metastatic melanoma patients; NSCLC patients; SCCHN or SCC(Small Cell Carcinoma) patients; hormone receptor positive/Human Epidermal growth factor Receptor-2 negative cancer patients

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with five diverse tumor histotypes (n=600) will be collected in parallel clinical case-sets, with power calculation estimated on the basis of MIS validation in melanoma (n=100 patients per histotypes, with the exception of the 200 patients to be enrolled for NSCLC). In addition, a group of age and gender-matched healthy donors (n=400) will be also included to provide normal values of the myeloid-related parameters under physiological conditions.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, 20033, Italy

RECRUITING

Related Publications (23)

• Huber V, Vallacchi V, Fleming V, Hu X, Cova A, Dugo M, Shahaj E, Sulsenti R, Vergani E, Filipazzi P, De Laurentiis A, Lalli L, Di Guardo L, Patuzzo R, Vergani B, Casiraghi E, Cossa M, Gualeni A, Bollati V, Arienti F, De Braud F, Mariani L, Villa A, Altevogt P, Umansky V, Rodolfo M, Rivoltini L. Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma. J Clin Invest. 2018 Dec 3;128(12):5505-5516. doi: 10.1172/JCI98060. Epub 2018 Nov 5.

  PMID: 30260323 BACKGROUND

• Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018 Mar 23;359(6382):1350-1355. doi: 10.1126/science.aar4060. Epub 2018 Mar 22.

  PMID: 29567705 BACKGROUND

• Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015 Dec 14;28(6):690-714. doi: 10.1016/j.ccell.2015.10.012.

  PMID: 26678337 BACKGROUND

• Apetoh L, Tesniere A, Ghiringhelli F, Kroemer G, Zitvogel L. Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res. 2008 Jun 1;68(11):4026-30. doi: 10.1158/0008-5472.CAN-08-0427.

  PMID: 18519658 BACKGROUND

• Peguillet I, Milder M, Louis D, Vincent-Salomon A, Dorval T, Piperno-Neumann S, Scholl SM, Lantz O. High numbers of differentiated effector CD4 T cells are found in patients with cancer and correlate with clinical response after neoadjuvant therapy of breast cancer. Cancer Res. 2014 Apr 15;74(8):2204-16. doi: 10.1158/0008-5472.CAN-13-2269. Epub 2014 Feb 17.

  PMID: 24535711 BACKGROUND

• Wilmott JS, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF, Kefford RF, Hersey P, Scolyer RA. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012 Mar 1;18(5):1386-94. doi: 10.1158/1078-0432.CCR-11-2479. Epub 2011 Dec 12.

  PMID: 22156613 BACKGROUND

• Steinberg SM, Shabaneh TB, Zhang P, Martyanov V, Li Z, Malik BT, Wood TA, Boni A, Molodtsov A, Angeles CV, Curiel TJ, Whitfield ML, Turk MJ. Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors. Cancer Res. 2017 Apr 1;77(7):1599-1610. doi: 10.1158/0008-5472.CAN-16-1755. Epub 2017 Feb 15.

  PMID: 28202513 BACKGROUND

• Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, Gherardini PF, Prestwood TR, Chabon J, Bendall SC, Fong L, Nolan GP, Engleman EG. Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell. 2017 Jan 26;168(3):487-502.e15. doi: 10.1016/j.cell.2016.12.022. Epub 2017 Jan 19.

  PMID: 28111070 BACKGROUND

• Dumeaux V, Fjukstad B, Fjosne HE, Frantzen JO, Holmen MM, Rodegerdts E, Schlichting E, Borresen-Dale AL, Bongo LA, Lund E, Hallett M. Interactions between the tumor and the blood systemic response of breast cancer patients. PLoS Comput Biol. 2017 Sep 28;13(9):e1005680. doi: 10.1371/journal.pcbi.1005680. eCollection 2017 Sep.

  PMID: 28957325 BACKGROUND

• Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C, Ryan RJ, Iwamoto Y, Marinelli B, Gorbatov R, Forghani R, Novobrantseva TI, Koteliansky V, Figueiredo JL, Chen JW, Anderson DG, Nahrendorf M, Swirski FK, Weissleder R, Pittet MJ. Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2491-6. doi: 10.1073/pnas.1113744109. Epub 2012 Jan 30.

  PMID: 22308361 BACKGROUND

• Gabrilovich DI. Myeloid-Derived Suppressor Cells. Cancer Immunol Res. 2017 Jan;5(1):3-8. doi: 10.1158/2326-6066.CIR-16-0297.

  PMID: 28052991 BACKGROUND

• Groth C, Hu X, Weber R, Fleming V, Altevogt P, Utikal J, Umansky V. Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression. Br J Cancer. 2019 Jan;120(1):16-25. doi: 10.1038/s41416-018-0333-1. Epub 2018 Nov 9.

  PMID: 30413826 BACKGROUND

• Ostrand-Rosenberg S. Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol. 2018 Apr;51:68-75. doi: 10.1016/j.coi.2018.03.007. Epub 2018 Mar 13.

  PMID: 29544121 BACKGROUND

• Wesolowski R, Markowitz J, Carson WE 3rd. Myeloid derived suppressor cells - a new therapeutic target in the treatment of cancer. J Immunother Cancer. 2013 Jul 15;1:10. doi: 10.1186/2051-1426-1-10. eCollection 2013.

  PMID: 24829747 BACKGROUND

• Fleming V, Hu X, Weber R, Nagibin V, Groth C, Altevogt P, Utikal J, Umansky V. Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression. Front Immunol. 2018 Mar 2;9:398. doi: 10.3389/fimmu.2018.00398. eCollection 2018.

  PMID: 29552012 BACKGROUND

• Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nat Rev Cancer. 2016 Jul;16(7):447-62. doi: 10.1038/nrc.2016.54.

  PMID: 27339708 BACKGROUND

• Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, Castelli C, Mariani L, Parmiani G, Rivoltini L. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol. 2007 Jun 20;25(18):2546-53. doi: 10.1200/JCO.2006.08.5829.

  PMID: 17577033 BACKGROUND

• Filipazzi P, Huber V, Rivoltini L. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother. 2012 Feb;61(2):255-263. doi: 10.1007/s00262-011-1161-9. Epub 2011 Nov 27.

  PMID: 22120756 BACKGROUND

• Blattner C, Fleming V, Weber R, Himmelhan B, Altevogt P, Gebhardt C, Schulze TJ, Razon H, Hawila E, Wildbaum G, Utikal J, Karin N, Umansky V. CCR5+ Myeloid-Derived Suppressor Cells Are Enriched and Activated in Melanoma Lesions. Cancer Res. 2018 Jan 1;78(1):157-167. doi: 10.1158/0008-5472.CAN-17-0348. Epub 2017 Oct 31.

  PMID: 29089297 BACKGROUND

• Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016 Jul 6;7:12150. doi: 10.1038/ncomms12150.

  PMID: 27381735 BACKGROUND

• De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, Proctor J, Kosmider N, White K, Stern H, Soglia J, Adams J, Palombella VJ, McGovern K, Kutok JL, Wolchok JD, Merghoub T. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature. 2016 Nov 17;539(7629):443-447. doi: 10.1038/nature20554. Epub 2016 Nov 9.

  PMID: 27828943 BACKGROUND

• Welters MJ, van der Sluis TC, van Meir H, Loof NM, van Ham VJ, van Duikeren S, Santegoets SJ, Arens R, de Kam ML, Cohen AF, van Poelgeest MI, Kenter GG, Kroep JR, Burggraaf J, Melief CJ, van der Burg SH. Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Sci Transl Med. 2016 Apr 13;8(334):334ra52. doi: 10.1126/scitranslmed.aad8307.

  PMID: 27075626 BACKGROUND

• Crunkhorn S. Cancer: New path to improving immunotherapy. Nat Rev Drug Discov. 2018 Mar;17(3):164. doi: 10.1038/nrd.2018.22. Epub 2018 Feb 16. No abstract available.

  PMID: 29449711 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Whole blood sample;if available, archival tumor biopsies: they will also be collected to perform the characterization of the immune infiltrate by immunohistochemistry (starting from CD8+(cytotoxic T lymphocytes)/CD163+ ratio) or by transcriptional profile, including IFN(Interferon) and adaptive immunity- related signatures.

MeSH Terms

Conditions

Melanoma; Breast Neoplasms; Carcinoma, Renal Cell; Urinary Bladder Neoplasms; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Small Cell

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Breast Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Urinary Bladder Diseases; Carcinoma, Squamous Cell; Head and Neck Neoplasms

Study Officials

• Licia Rivoltini

  Fondazione IRCCS Istituto Nazionale Tumori - Milan

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Licia Rivoltini

CONTACT

+3902/23903245; licia.rivoltini@istitutotumori.mi.it

Paola Frati

CONTACT

+3902/23903036; paola.frati@gmail.com

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 3, 2022
• First Posted: November 18, 2022
• Study Start: March 10, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: May 2, 2025

Record last verified: 2025-04

Locations

IT (1)