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Combination immune checkpoint inhibition (ICI) with antibodies targeting PD-1 and CTLA-4 provides superior outcomes compared to either monotherapy alone. This combination has been approved for advanced melanoma, metastatic colon cancer and others. However, combination therapy with anti-PD-1/CTLA-4 antibodies results in serious immune related adverse events (irAEs), presenting an obstacle for effective treatment with combination systemic anti-PD-1/CTLA-4. Intratumoral (IT) immunotherapy is a strategy to enhance local activity while decreasing systemic irAEs. While clinical testing of IT antibodies is underway, antibodies' high molecular weight may limit their local diffusion and retention time within tumors. RNAi is an emerging therapeutic modality well-suited for local clinical application of ICI. We have demonstrated that self-delivering RNAi therapeutics built on proprietary INTASYL™ technology specifically silence their targets in tissues without need for specialized formulations or delivery systems, and convey robust antitumor efficacy in vivo. Furthermore, multiple INTASYL compounds can be easily co-formulated into a multi-targeting therapeutic, providing specific silencing of multiple therapeutic targets in a single injection. Here, we present proof-of-concept (POC) in vivo data demonstrating synergistic efficacy of a novel INTASYL dual-targeting murine PD-1 (mPH-762) and CTLA-4 (27790) coformulation in PBS in a syngeneic CT26 model of murine colon cancer. Dual on-target silencing was first validated in murine T cells in vitro. In vivo, CT26 cells were implanted subcutaneously into female BALB/c mice. Vehicle (PBS) or INTASYL IT treatment commenced when tumors reached a mean threshold volume (150 mm3; Day 1) with doses given on Days 1, 4, 7, 10, and 13. Mice received a total 1 mg/dose with the dual-targeting INTASYL, comprised of 0.5 mg of each compound. Another group received the dual-targeting INTASYL at 2 mg/dose. Tumor volumes and body weights were recorded longitudinally and analyzed by area under the curve (AUC). Tumors were isolated on Day 15 and mechanistic immunomodulation of the tumor microenvironment (TME) was assessed by flow cytometry. IT INTASYL dual-targeting PD-1 and CTLA-4 elicited robust dose-associated antitumor efficacy that was superior to the identical total dose of either single-targeting INTASYL, when comparing mean tumor volume AUC, demonstrating antitumor synergy by the dual-targeting coformulation. On-target mechanistic immunomodulatory effects were observed in the TME. These data demonstrate POC synergistic efficacy of IT INTASYL dual-targeting CTLA-4/PD-1 in vivo, supporting further development to maximize efficacy and minimize irAEs. PH-762 is currently under clinical investigation in a Phase 1b study for advanced melanoma. Citation Format: Benjamin G. Cuiffo, Andrew Boone, Dingxue Yan, Melissa Maxwell, Brianna Rivest, James Cardia, Simon P. Fricker. INTASYL self-delivering RNAi therapeutic dual targeting PD-1 and CTLA-4 provides synergistic antitumor efficacy in the treatment of murine colon cancer in vivo. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5113. |
