BACKGROUND: RRx-001, a novel oxidizing and epigenetic agent, has shown promise as a single agent in a Phase I trial and is currently in Phase II trials, both alone and in combination with immunotherapy (Nivolumab), chemotherapy and radiation therapy.
OBJECTIVE: The primary objective of the experiments described here was to test the hypothesis that RRx-001 combined with the checkpoint inhibitor, anti-PD-L1 would increase the complete response (CR) rate in a preclinical model of myeloma.
METHODS and RESULTS: BALB/c mice with well established J558L myeloma tumors (100-150 mm3 in volume) were treated with anti-PD-L1 antibody alone (10 mg/kg, i.p., twice a week for two weeks), RRx-001 alone (10 mg/kg, i.p., two doses on Day 0 and day 4) or the combination of anti-PD-L1 + RRx-001. Tumors were measured every other day and tumor response as well as the tumor volume quadrupling time (4X TGT) were calculated. In an initial pilot experiment with 4 mice/group, the combined therapy group had the best response compared to either treatment alone or the untreated control group. In a larger duplicate experiment with 8-10 mice/group, the CR rate was 0%, 37.5%, 22.2% and 75% for the untreated control, anti-PD-L1, RRx-001, and combined group, respectively. In terms of a comparison of the 4X TGT, RRX-001 + anti-PD-L1 was more efficacious than the untreated control (P < 0.01), RRx-001 alone (P = 0.01) and anti-PD-L1 alone (P = 0.1).
CONCLUSIONS: These results demonstrate that inhibition of the PD-1/PD-L1 axis in combination with RRx-001 can significantly increase the CR rate in a preclinical model of myeloma. Experiments are ongoing to optimize this treatment regimen, study the effects of the combined treatment on the tumor immune microenvironment, and the study the efficacy of this combined therapy in other tumor types. Results from this ongoing work will be presented, and have near term translational potential.
Citation Format: Susan J. Knox, Shoucheng Ning, Donna Peehl, Bryan Oronsky, Jan Scicinski. RRx-001 combined with anti-PD-L1 antibody increases the complete response rate in a preclinical myeloma model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C181.