Nivolumab in mRCC Patients: Treg Function, T-cell Access and NK Interactions to Predict and Improve Efficacy (REVOLUTION)

The project aims to identify Nivolumab predictive biomarkers in metastatic renal cancer patients through functional evaluation of peripheral Tregs and NKs. Moreover the efficacy of new CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/ US2013/0079292A1) will be ex vivo evaluated in modulating Tregs and NKs function

Study Overview

• Status: Recruiting
• Conditions: Metastatic Renal Cell Carcinoma; RCC
• Intervention / Treatment: Biological: Immunological and tumour characterization

Detailed Description

Renal cell carcinomas (RCCs) is a disease with an estimated 338,000 new cases diagnosed worldwide. Approximately 30% of patients present with metastatic disease. Since November 2015 the human IgG4 anti-PD-1 monoclonal antibody, Nivolumab, was approved to treat advanced (metastatic) clear cell renal cell carcinoma (ccRCC) patients who have received a prior anti-angiogenic therapy. PD-1 (also know as CD279), is an immune checkpoint receptor (ICR) expressed on the surface of T cells. The binding with its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) expressed on tumour cells, stromal cells or both suppress effector T cells activation and inflammatory activity promoting self-tolerance and allowing cancer cells to evade immune system. Despite encouraging results in multiple solid tumors the clinical anti-PD1 response is not as wide as expected due to multiple immuno-escape mechanisms; moreover there aren't biomarkers to predict or follow RCC patient's response to Nivolumab.

Immune evasion comprise the recruitment of immunosuppressive cells and reduced access of T-effector cells to tumor microenvironment. T-regulatory cells (Tregs) suppress a whole range of immune cells and ICRs regulate generation and/or suppression of their function. Immune cell access to tumor is controlled by the chemokine CXCL12, CXCR4 ligand. CXCL12 repels tumor-specific effector T cells and recruits suppressive cell populations at tumor sites. von Hippel-Lindau (VHL) gene mutations, detectable in 70% of RCC patients, regulate immune response inducing PD-L1 expression and promoting Natural Killer (NK) cells function. Thus NK function is a crucial element in nivolumab sensitivity.

The project will enroll patients receiving Nivolumab in 2nd or 3rd line treatment for metastatic ccRCC and, as control cohorts, either everolimus or axitinib.

Aims of the project are:

• To evaluate Tregs function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment. Ex vivo effect of CXCR4 antagonists (PCT/IB2011/000120/ EP2528936B1/ US2013/0079292A1) and other Tregs targets antagonists (ICOS,CD39/CD73) or agonists (TLR7L) as putative anti-PD1 resistance mechanisms
• To evaluate NK function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment. Ex vivo effect of CXCR4 antagonists

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Stefania Scala, MD, PhD; Phone Number: 0815903820; Email: s.scala@istitutotumori.na.it

Study Locations

• Italy
  • Naples, Italy, 80131
    • Recruiting
    • IRCCS Istituto Nazionale Tumori di Napoli
    • Principal Investigator: Sandro Pignata, MD, PhD
    • Contact: Stefania Scala, MD, PhD; Phone Number: 0815903820; Email: s.scala@istitutotumori.na.it
    • Principal Investigator: Stefania Scala, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Men and women with histological confirmation of advanced/metastatic RCC

Description

Men and women with histological confirmation of advanced/metastatic RCC with not more than 2 previous therapy lines

Inclusion Criteria:

• Age ≥ 18 years-old.
• Histology proven locally advanced (unresectable) or metastatic clear cell renal cell carcinoma (mccRCC).
• Starting 2nd or 3rd line of treatment with nivolumab, everolimus or axitinib
• Signed informed consent.

Exclusion Criteria:

• Psychological, familial, sociological, geographical conditions that would limit compliance with study protocol requirements.
• Pregnant or breastfeeding woman

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tregs function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment.	Treg function will be mesured as % inhibition of T-effector proliferation (Tregs/T-effector 1:1 ratio). %T-effector proliferation in the presence of patients derived Tregs (Tregs/T-effector 1:1). Ex vivo effect of CXCR4 antagonists ( PCT/IB2011/000120; EP 2 528 936 B1/US2013/0079292A1) and other Tregs targets antagonists (ICOS, CD39/CD73) or agonists (TLR7L) will be assessed to identify novel anti-PD1 resistance mechanisms.	Evolution between inclusion up to 24 months
NK function/cytotoxicity on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment	NK cytotoxicity will be measured as % NK cell degranulation (CD107a assay), intracellular staining Grz A and GrzB and intracellular cytokines, GM-CSF, IFNγ, IL-10, TNF. Ex vivo effect of CXCR4 antagonists will be evaluated on NK cytotoxicity.	Evolution between inclusion and up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploration of the biological rationale for coupling CXCR4 antagonist with anti-PD-1 in in vivo models of RCC (mice models)	The effect of anti-PD1 and CXCR4 antagonists on tumor and tumor microenvironment cells will be evaluated in: Immunocompetent model (RENCA): % tumor growth; % positive cells Granzyme/ Foxp3; Human xenograft model (786 cell): % tumor growth	36 months

Collaborators and Investigators

• Sponsor: National Cancer Institute, Naples

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: February 26, 2019
• First Submitted That Met QC Criteria: March 23, 2019
• First Posted (Actual): March 27, 2019

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Nivolumab; mRCC; CXCR4 antagonist; Tregs-NKs
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell
• Other Study ID Numbers: 21/16 oss

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No