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Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

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Nivolumab

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FFPE, blood samples (liquid biopsy, heparin and EDTA blood) performed in patients presenting a renal metastatic cancer receiving treatment as standard practice according to physician's choice (2nd or 3rd line of treatment with nivolumab, or other second line according to physician's choice)

Immunological and tumour characterization

Stefania Scala, MD, PhD

Sandro Pignata, MD, PhD

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

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

Archival FFPE specimen.

Blood samples performed during standard visits and not requiring additional blood tests:

* Heparin blood
* EDTA blood

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

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.

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.

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

National Cancer Institute, Naples

Everolimus

Axitinib

Immunomodulating Agents

Sunitinib

FFPE, blood samples (liquid biopsy, heparin and EDTA blood) performed in patients presenting a renal metastatic cancer receiving treatment as standard practice according to physician's choice (2nd or 3rd line of treatment with nivolumab, everolimus, axitinib or cabozantinib \[in France only\], as per product SmPC or 1st line treatment with sunitinib or pazopanib or receiving 2nd or 3rd line of treatment with nivolumab)

BLANC Ellen

BOYLE J Helen, MD

BOYLE Ellen, MD

The BIOREN project aims are to characterize the genetic background of renal cell carcinomas and their immune environment, to try and identify biomarkers of response and to better understand the mechanisms of resistance to nivolumab in renal cancer.

Around 338,000 new cases of renal cell carcinoma (RCC) are diagnosed worldwide per year (1). RCC is one of the most immune responsive human cancers. For a long time the only available treatment were high-dose IL-2 and IFN-α with only a few patients achieving durable responses. Clinical trials conducted in the past 15 years have led to the approval of several anti-angiogenic treatments, mainly vascular endothelial growth factor receptor (VEGFR) inhibitors and mTOR inhibitors. Currently most patients receive first line anti-VEGF therapy.

Recently a better understanding of the mechanisms by which tumours evade the immune system has led to the development of checkpoint inhibitors, such as anti CTLA-4, anti-PD-1 and anti-PD-L1 antibodies that have been tested in various tumour types.

Recently, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved the human IgG4 anti-PD1 monoclonal antibody, nivolumab, for advanced/metastatic clear cell RCC (ccRCC) patients who have received prior antiangiogenic therapy. PD-1 is a key immune-checkpoint receptor (ICR) expressed by activated T cells, which mediates immunosuppression primarily in peripheral tissues, where T cells may encounter the immunosuppressive PD-1 ligands, PD-L1 (B7-H1) and PD-L2(B7-DC) on tumour cells, stromal cells or both.

Despite encouraging results, the clinical response to anti-PD1 is not as wide as expected and there are not any biomarkers 1) that are able to predict which patients will respond and 2) that predict response to nivolumab in patients with ccRCC.

BIOREN is a translational, prospective, observational 3-cohort study.

The aims of BIOREN are to characterize the genetic background of the tumours and also their immune environment, to try and identify biomarkers of response and to better understand the mechanisms of resistance to nivolumab in renal cancer. We will focus on:

* Tregs function and modulation of function,
* NK cells known to be regulated by nivolumab,
* The biological rationale for coupling CXCR4 antagonist with anti PD-1 therapy, analysed with mice models,
* To try to identify biomarkers of response by further characterization of the tumours and evaluating the immune status.

The project will enrol patients receiving in 2nd or 3rd line treatment for metastatic ccRCC: Nivolumab but also, as control cohorts, either everolimus or axitinib (approved treatments in this setting), as well as cabozantinib in France (recently approved in 2nd or 3rd line).

French blood samples and archival FFPE (formalin-fixed paraffin embedded) specimens will be analysed in in France, and also sent to the partners of the Transcan project Consortium (Israel, Italy and Spain).

Archival FFPE specimen

Blood samples performed during standard visits and not requiring additional blood tests:

* Heparin blood (4 x 6ml)
* EDTA blood (5 x 6ml)
* Liquid biopsy (EDTA) (5 x 6ml)

BIOREN (Predictive BIOmarkers in Metastatic RENal Cancer)

BIOREN (Predictive BIOmarkers in Metastatic RENal Cancer) - A Translational Study on Immunotherapy for Metastatic Renal Cancer

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

NK cytotoxicity will be evaluated through NK cell degranulation (CD107a assay), intracellular staining of the lytic proteins, Grz A and GrzB and intracellular cytokines, GM-CSF, IFNγ, IL-10, TNF. NK cell will be characterized for CXCR4; maturation markers: CD16, CD56, CD57, CD62L, NKG2A; activating receptors markers: CD25, CD69, NKp44, NKp30, NKp46, NKG2D. Ex vivo effect of CXCR4 antagonists on NK cytotoxicity.

immunocompetent model (RENCA), human xenograft model (786 cell) and humanized model

Characterization of the tumours using different techniques (RNASeq whole genome, NGS analysis, IHC, HTG focus RNAseq)

Immune status (Multi-IF analysis, TCR sequencing and clonality analysis, Anti-HERV T cell and humoral response)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab in mRCC Patients: Treg Function, T-cell Access and NK Interactions to Predict and Improve Efficacy	NCT03891485	RCC Metastatic Rena...	Immunological a...	-	National Cancer Institute, Naples
BIOREN (Predictive BIOmarkers in Metastatic RENal Cancer)	NCT03628859	Renal Cancer Me...	Immunological a...	18 Years -	Centre Leon Berard
BIOREN (Predictive BIOmarkers in Metastatic RENal Cancer)	NCT03628859	Renal Cancer Me...	Immunological a...	18 Years -	Centre Leon Berard

Spots Global Cancer Trial Database for immunological and tumour characterization