Abstract 1792P
Background
Targeting the bromodomain and extra-terminal motif (BET) protein BRD4 is an attractive target for cancer immunotherapy, as it exerts impacts on both cancer cells and T cells. Preclinical data suggests added therapeutic potential in co-targeting the immune checkpoint PD-1. INTASYL™ is a self-delivering RNAi platform that provides both highly efficient delivery to target cells without need for specialized drug delivery systems and strong gene silencing of multiple targets in a single drug formulation. We have demonstrated enhanced anti-tumor efficacy in vivo by directly co-targeting multiple rational targets via intratumoral (IT) administration, including INTASYL co-targeting murine/human BRD4 (PH-894) and murine PD-1 (mPH-762) (PH-894/mPH-762) in a preclinical Hepa1-6 model of murine hepatoma (HCC). Here we report the results of a rechallenge phase of that study for mice with stable complete resolution (CR, "cure") of tumors following PH-894/mPH-762 treatment, providing evidence of persistent anti-tumor immunity elicited by IT INTASYL treatment.
Methods
Subcutaneous Hepa1-6 tumors in C57BL/6N mice were treated with INTASYL PH-894/mPH-762 by IT injection. Cured mice or naïve controls were rechallenged 29 days post-treatment with an identical inoculum (1e07) of Hepa1-6 cells to the contralateral flank relative to the primary tumor. No additional treatment was provided. Longitudinal tumor measurements and body weights were recorded.
Results
Local treatments with PH-894/mPH-762 resulted in stable CR of 83% (10/12) of the tumors. While rechallenge tumors (rTs) of naïve animals grew steadily as expected, 100% of rTs of mice previously cured by INTASYL PH-894/mPH-762 first grew but then diminished to CR over Day 12-40. These results and further analyses suggest that mice cured by INTASYL PH-894/mPH-762 developed durable systemic immunity to the Hepa1-6 tumors.
Conclusions
These data show that, in addition to eliciting stable complete resolution, dual-targeting IT treatment with INTASYL PH-894/mPH-762 engenders durable systemic anti-tumor immunity and supports a planned clinical study to start later this year in France.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Phio Pharmaceuticals.
Funding
Phio Pharmaceuticals.
Disclosure
B. Cuiffo, M. Maxwell, D. Yan, B. Rivest, J. Cardia, S.P. Fricker: Financial Interests, Institutional, Full or part-time Employment: Phio Pharmaceuticals.