Self-delivering RNAi immunotherapeutic PH-762 silences PD-1 to generate local and abscopal antitumor efficacy.

Autor:	Cuiffo B; Phio Pharmaceuticals, Marlborough, MA, United States., Maxwell M; Phio Pharmaceuticals, Marlborough, MA, United States., Yan D; Phio Pharmaceuticals, Marlborough, MA, United States., Guemiri R; Dermatology Unit, Gustave Roussy Cancer Center, Villejuif, France., Boone A; Phio Pharmaceuticals, Marlborough, MA, United States., Bellet D; Dermatology Unit, Gustave Roussy Cancer Center, Villejuif, France., Rivest B; Phio Pharmaceuticals, Marlborough, MA, United States., Cardia J; Phio Pharmaceuticals, Marlborough, MA, United States., Robert C; Dermatology Unit, Gustave Roussy Cancer Center, Villejuif, France., Fricker SP; Phio Pharmaceuticals, Marlborough, MA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Dec 04; Vol. 15, pp. 1501679. Date of Electronic Publication: 2024 Dec 04 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1501679
Abstrakt:	Objective: Immunotherapeutic inhibition of PD-1 by systemically administered monoclonal antibodies is widely used in cancer treatment, but it may cause severe immune-related adverse events (irSAEs). Neoadjuvant PD-1 inhibition before surgery has shown promise in reducing recurrence by stimulating durable antitumor immunity. Local intratumoral (IT) immunotherapy is a potential strategy to minimize irSAEs, but antibodies have limited tumor penetration, making them less suitable for this approach. Therapeutic self-delivering RNAi (INTASYL) is an emerging modality well-suited for neoadjuvant immunotherapy. This study presents preclinical proof-of-concept for PH-762, an INTASYL designed to silence PD-1, currently in clinical development for advanced cutaneous malignancies (ClinicalTrials.gov#NCT06014086). Methods and Analysis: PH-762 pharmacology was characterized in vitro , and in vivo antitumor efficacy was evaluated using a murine analogue (mPH-762) in syngeneic tumor models with varying PD-1 responsiveness. Bilateral Hepa1-6 models assessed abscopal effects of local treatment. Ex vivo analyses explored mechanisms of direct and abscopal efficacy. Results: PH-762 was rapidly internalized by human T cells, silencing PD-1 mRNA and decreasing PD-1 surface protein, enhancing TCR-stimulated IFN-γ and CXCL10 secretion. In vivo , IT mPH-762 provided robust antitumor efficacy, local and lymphatic biodistribution, and was well tolerated. Ex vivo analyses revealed that IT mPH-762 depleted PD-1 protein, promoted leukocyte and T cell infiltration, and correlated with tumor control. IT mPH-762 also demonstrated efficacy against untreated distal tumors (abscopal effect) by priming systemic antitumor immunity. Conclusion: These data support PH-762 as a promising candidate for neoadjuvant immunotherapy in clinical studies. Competing Interests: Authors BC, MM, DY, RG, AB, BR, JC, and SF were employed by Phio Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Cuiffo, Maxwell, Yan, Guemiri, Boone, Bellet, Rivest, Cardia, Robert and Fricker.)
Databáze:	MEDLINE
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