Abstract 580: Nivolumab treatment of metastatic renal cancer patients impairs Tregs and potentiates NK function: The role of CXCR4 inhibition (“REVOLUTION Trial”)

Abstract

Abstract Despite encouraging results, Nivolumab response is not as wide as expected in renal cancer ( RCC). Among mechanisms of immunoresistance T-regulatory cells(Tregs) activity plays a central role. We previously showed that tumoral Tregs in RCC patients are more suppressive than healthy donors Tregs. Since tumoral Tregs express high level of CXCR4, the receptor antagonism was evaluated on patients Tregs revealing that CXCR4 antagonism reverted Treg suppressive activity( Santagata et al, submitted manuscript). To identify biomarkers informative and predictive of nivolumab efficacy Treg function, tumoral access and NK interactions was determined in nivolumab treated mRCC patients (“ Revolution” trial). At today eleven patients were analyzed for Tregs and NKs function at time 0-2-4 weeks-3-6 months of treatment. 2 patients died for unrelated causes, 5 Patients showed PR, 4 SD and 1 PD at six months. At time 0 Tregs function, evaluated as inhibition of T-effector (Teff) proliferation, varied among patients; two patients showed anergy reversed by Nivolumab treatment. Overall, increase in Teff proliferation, compatible with a decreased Tregs activity, was revealed during nivolumab treatment and, while the total peripheral Tregs was unaffected, a decrease in CD4+CD25+127lowFOXp3 highCD45RA - (suppressive Tregs) was detected. NK activity, evaluated as CD107a exposure, increased with nivolumab treatment with a concomitant reduction in the inhibitory receptors CD158a, PD-1 and CXCR4. Moreover patients Tregs and NKs were evaluated in vitro for the efficacy of CXCR4 inhibition in affecting cell function. CXCR4 antagonists suppressed the Treg mediated inhibition of Teff proliferation. In conclusion the evaluation of 11 patients enrolled in the REVOLUTION study revealed detectable variations on Tregs and NKs function relatively to Nivolumab treatment to be correlated with clinical outcome. Tregs suppressive function was impaired by inhibition of CXCR4 receptor. Citation Format: Sara Santagata, Anna Maria Trotta, Maria Napolitano, Luigi Portella, Sabrina Rossetti, Sisto Perdona, Sandro Pignata, Stefania Scala. Nivolumab treatment of metastatic renal cancer patients impairs Tregs and potentiates NK function: The role of CXCR4 inhibition (“REVOLUTION Trial”) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 580. doi:10.1158/1538-7445.AM2017-580