Prediction of Nivolumab action in metastatic renal cancer patients: Treg function, tumoral access and NK interaction as predictive biomarkers of immunotherapy
Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"
Napoli - Italy
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.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.