RE-VOLU-TION

Anti-PD1 Nivolumab is approved to treat advanced/metastatic renal carcinoma (mRCC) patients following anti-angiogenic therapy.
Despite encouraging results, Nivolumab response is not as wide as expected. Immune evasion is driven by multiple mechanisms
comprising 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 immune-checkpoint receptors (ICRs) regulate generation and suppressive
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.VHL mutations, detectable in ~70% of RCC patients, regulate immune
response inducing PD-L1 expression and promoting NK function. Thus NK function is a crucial element in nivolumab sensitivity.
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
•To explore the biological rationale for coupling CXCR4 antagonist with anti PD-1 in in vivo models of renal cancer
We aim to enroll 200 patients with mRCC, 1/3 treated with Nivolumab and 1/3 with everolimus or axitinib. Mice models will shed further
insights into the mechanism of combined targeting of anti PD-1 plus CXCR4 antagonists dissecting the effects on immune versus
tumoral cells.
We expect to identify biomarkers that selectively represent and predicts Nivolumab sensitivity.The efficacy of CXCR4 antagonism
could monitor the efficacy of cancer immunotherapy and seed the basis for combined therapy.