TPS711 Background: Checkpoint inhibitor immunotherapy directed at PD1/PDL1 has shown clinical efficacy in advanced clear cell Renal Cell Cancer (ccRCC). However, only a minority of patients respond to anti-PD1 monotherapy. There is an urgent unmet need to improve response rates including through rational combinations to reverse immune evasion by tumors. The chemokines CXCL9 and CXCL10 in the tumor micro-environment are chemo-attractants for activated NK and Th1 cells and are critical for anti-tumor immunity. Preclinical data from our group showed hypermethylation induced silencing of CXCL9/10 signaling is an important tumor immune evasion mechanism. In RCC cell lines (A-498, HTB-46 and CRL-1611), hypomethylating agents increased CXCL9/10. In mouse xenograft models, combination therapy with a hypomethylating agent and checkpoint inhibitors led to higher levels of CXCL 9/10, reversal of immune evasion and potent tumor regression. We hypothesized that the combination of guadecitabine (hypomethylating agent) with durvalumab (anti-PDL1 antibody) would increase T lymphocyte infiltration into RCC tumors including those that are immunologically ‘cold’ and result be effective in 1st and 2nd line RCC. Methods: The study is a single arm, multi-site, phase 1b/2 trial through the Big Ten Cancer Research Consortium of Guadecitabine (starting dose of 60 mg/m2/dose subcutaneously on days 1-5) with Durvalumab (1500 mg IV on day 8) in 28-day cycles in pts with metastatic ccRCC. Cohort 1 (N = 36) will consist of pts naïve to checkpoint inhibitor immunotherapy and 0-1 prior therapies. Cohort 2 (N = 16) will include pts who did not respond to prior anti-PD-1/PD-L1 therapy. The primary endpoint is objective response rate by RECIST 1.1 in cohort 1. Statistical analysis will use a binomial exact test to compare the ORR proportion in patients treated in Cohort 1 with the combination compared to an expected proportion of 25% with anti-PDL1 alone. The extensive correlative objectives include serial evaluation of serum CXCL9/10 levels and LINE-1 methylation status as well as tumor infiltrating lymphocytes profiling, PD-L1 expression, tumor mutational burden and NGS on mandatory baseline and optional biopsies at progression. Clinical trial information: NCT03308396.
Interferon-Independent Activities of Mammalian STING Mediate Antiviral Response and Tumor Immune Evasion
