Clinical trial NCT03891485: Nivolumab in mRCC Patients: Treg Function, T-cell Access and NK Interactions to Predict and Improve Efficacy
Official title: Nivolumab in mRCC Patients: Treg Function, T-cell Access and NK Interactions to Predict and Improve Efficacy
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: RCC
Metastatic Renal Cell Carcinoma
Keywords: Nivolumab
CXCR4 antagonist
mRCC
Tregs-NKs
Lead sponsor: National Cancer Institute, Naples
Sponsor class: OTHER
First posted: 2019-03-27
Enrollment: 200
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Men and women with histological confirmation of advanced/metastatic RCC

Brief summary: 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

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

Eligibility criteria: 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

Primary outcomes:
measure: Tregs function on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment.
timeFrame: Evolution between inclusion up to 24 months
measure: NK function/cytotoxicity on peripheral blood/neoplastic tissue from mRCC patients undergoing nivolumab treatment
timeFrame: Evolution between inclusion and up to 24 months
Secondary outcomes:
measure: Exploration of the biological rationale for coupling CXCR4 antagonist with anti-PD-1 in in vivo models of RCC (mice models)
timeFrame: 36 months
Other outcomes:
Locations:
city: Naples
country: Italy
facility: IRCCS Istituto Nazionale Tumori di Napoli
Study officials:
References: