Clinically relevant molecular subgroups of prostate cancer bone metastases

Background: Combination strategies are required to improve outcomes for immune mediated anti-tumor therapies. Entinostat is a class 1 selective histone deacetylase inhibitor shown in preclinical studies to target immune suppressive mechanisms in the tumor microenvironment to improve the efficacy of immune checkpoint blockade, vaccines and cytokines. NKTR-214 is a novel CD122-biased agonist with promising safety, tolerability and anti-tumor efficacy. A previous phase 2 clinical trial of entinostat combined with high dose interleukin 2 demonstrated enhanced clinical efficacy and a well-tolerated safety profile in advanced renal cell cancer patients. Based on these data and potential for combinatorial anti-tumor activity, we investigated the antitumor efficacy and immune response of entinostat combined with NKTR-214 in CT26 colon cancer and RENCA renal cell cancer syngeneic tumor models. Methods: CT26 and RENCA cells were subcutaneously inoculated into 6-8-week-old BALB/c mice (n=12 per arm) and when tumors reached ~140mm 3 were randomized and treated with entinostat (p.o., 1 mg/kg or 5 mg/kg, QD x 28), NKTR-214 (i.v., 0.8mg/kg, Q9D x 4), the combination, or vehicle control. Phenotypic and functional analysis of tumor infiltrating cells in each group was conducted on tumors taken from 3 mice per arm, at day 7 post-treatment. Remaining mice (n=9 per arm) continued treatment until tumors reached 2,000mm 3 . Results: In the CT26 model, the combination of entinostat (1mg/kg and 5mg/kg) and NKTR-214 was tolerated and demonstrated prolonged survival with a medium survival time not reached for the combination groups (7 of 9 animals still alive) as compared to NKTR-214 (44 days; 3 of 9 alive), entinostat or controls (16 days; none living). In RENCA, the treatments were less well tolerated and tumor growth inhibition is reported only for the entinostat 1mg/kg dose level with that combination demonstrating 60% tumor growth inhibition (n=8), compared to 34% in NKTR-214 alone (n=8), or 27% in entinostat alone (n=8) arms. Analysis of tumor infiltrating immune and myeloid cells after treatment indicated no significant phenotypic changes in any of the cell populations studied. However, measurement of IFNγ, TNFα and Granzyme B expression in T cell and NK cells revealed enhanced anti-tumor cytotoxicity. IFNγ was increased u003e15-fold in CT26 and u003e9-fold in RENCA treated with the entinostat (5mg/kg) and NKTR-214 combination along with increases in granzyme B (CT26 u003e17-fold; RENCA u003e 166-fold) and TNFα (CT26u003e3-fold; RENCA u003e2-fold). Conclusions: These data demonstrate that entinostat combined with NKTR-214 results in enhanced cytotoxic Teff function which translates to significant anti-tumor effects. These results provide support for clinical testing of the combination with or without additional immune checkpoint blockade. Citation Format: Lei Wang, Fei Chen, Tingting Li, Peter Ordentlich, Jonathan Zalevsky. Enhanced anti-tumor activity of the combination of entinostat and NKTR214 in renal and colon cancer tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 123.