Abstract 4237: Local administration of BRD4-targeting self-delivering RNAi (PH-894) provides abscopal efficacy toward untreated distal tumors and potentiates the efficacy of systemic anti-PD-1 antibody therapy
Authors: Cuiffo Benjamin , Maxwell Melissa , Yan Dingxue , Zhou Shenghua , Rivest Brianna , Boone Andrew , Cardia James , Fricker Simon P. 
Published: June 2022

Abstract
Immune checkpoint inhibitor (ICI) anti-PD-1 antibody (mAb) monotherapy represented a significant advancement in cancer treatment, however most patients will ultimately progress, signaling the need for improvement. Combination approaches with other ICI mAbs may improve outcomes, however, systemic administration of immunostimulatory mAb combinations further increases risk for treatment-induced immune related adverse effects (irAEs). We have previously shown that intratumoral (IT) administration of PH-894, a self-delivering RNAi compound targeting BRD4 built on proprietary INTASYL™ technology, imparts tumor control in vitro and in vivo via effects on both T cells and tumor cells. Local priming of the immune response has shown promise toward potentiating the impact of systemic immunotherapy; therefore, we hypothesized that IT PH-894 might potentiate the efficacy of systemic anti-PD-1 mAb therapy. To assess this in vivo, an identical inoculum (5e05) of CT26 cells was implanted subcutaneously into the bilateral flanks of BALB/c mice. Vehicle (PBS; IT), anti-PD-1 mAb (0.1 mg/dose; intraperitoneal (IP)), PH-894 (0.5 mg/dose; IT) or combination anti-PD-1 mAb (0.1 mg/dose; IP) + PH-894 (0.5 mg/dose; IT) were administered, with IT doses limited to the tumor on the left flank only, on Days 1, 4, 7, 10 and 13. Tumors on the opposite flank were left untreated. Tumor volumes and body weights were recorded. Tumors, spleens, and lymph nodes were isolated for ex vivo mechanistic studies. The abscopal effects of IT PH-894 were confirmed in a bilateral Hepa1-6 model of murine hepatoma. In the CT26 model, as expected, growth of both tumors was inhibited with systemic anti-PD-1. Treatment with IT PH-894 provided a similar level of tumor control compared to treatment with IP anti-PD-1 mAb, both for the PH-894 directly-treated tumors, but in addition also towards the PH-894 untreated distal tumors, an abscopal impact. Additionally, IT PH-894 enhanced the antitumor efficacy of systemic anti-PD-1 mAb therapy, not only for the PH-894 locally treated tumors, but for the PH-894 untreated distal tumors. These data show that IT administered PH-894 potentiated the efficacy of systemic anti-PD-1 mAb, both locally and toward PH-894 untreated distal tumors. In addition, PH-894 silencing of BRD4 not only inhibited tumor growth at the local site of therapy, but also elicited an abscopal effect toward distal tumors, with efficacy similar to that provided by systemically administered anti-PD-1 mAb. These results indicate that IT PH-894 can potentiate the efficacy of systemic anti-PD-1 mAb, warranting further investigation of clinical applications in combination with anti-PD-1 mAbs toward improving patient outcomes.
Citation Format: Benjamin Cuiffo, Melissa Maxwell, Dingxue Yan, Shenghua Zhou, Brianna Rivest, Andrew Boone, James Cardia, Simon P. Fricker. Local administration of BRD4-targeting self-delivering RNAi (PH-894) provides abscopal efficacy toward untreated distal tumors and potentiates the efficacy of systemic anti-PD-1 antibody therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4237.