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<h3>Background</h3> INTASYL™ is a patented, self-delivering RNAi technology enabling efficient delivery of small interfering RNAs to a broad range of cells and tissues without the need for specialized formulation enhancements or manipulations. INTASYL’s innovative chemical design potentially minimizes toxicity risks while enhancing both tolerability and efficacy. PH-762, an INTASYL compound, precisely silences PD-1 mRNA to enhance immune responses by relieving T cell exhaustion, thereby improving their ability to target and eliminate tumor cells. For treatment of cutaneous carcinomas, PH-762 can be administered via intratumoral (IT) injection, which is anticipated to diminish the systemic side effects associated with conventional systemic anti-PD-1 antibody treatments. PH-762’s unique structural and chemical modifications ensure an optimized cell and tissue uptake profile with IT administration. <h3>Materials and Methods</h3> In vitro studies assessed the uptake of PH-762 in human T cells, followed by the assessment of silencing of PD-1 at mRNA and protein levels. Preclinical studies in murine models evaluated the effects of murine-targeted PH-762 (mPH-762), focusing on PD-1 mRNA silencing in tumor-infiltrating T cells and enhanced IFN-γ secretion. Toxicokinetic studies were conducted in marmoset monkeys with IV doses up to 147 mg/kg followed by analysis for cytokine-release-associated cytokines in plasma. PH-762 is currently being investigated in an open-label clinical study (NCT 06014086) to evaluate the safety and tolerability of neoadjuvant use of IT PH-762 in cutaneous squamous cell carcinoma (cSCC), melanoma, or Merkel cell carcinoma. The study will assess the pharmacokinetic profile of PH-762 after IT injection, to observe pathologic and immunologic tumor responses, and to determine the recommended dose for continued clinical development. <h3>Results</h3> In vitro studies demonstrated rapid uptake of PH-762 in human T cells, leading to significant silencing of PD-1 mRNA and protein levels. Preclinical data demonstrated that IT mPH-762 significantly inhibited tumor growth and was well-tolerated at the maximum administered dose. Toxicokinetic studies confirmed that PH-762 was well-tolerated, with no detectable cytokine-release-associated cytokines in plasma. In the ongoing clinical trial, PH-762 is administered as a neoadjuvant IT therapy, with preliminary data assessing safety, pharmacokinetics, tumor responses, and immunological outcomes. <h3>Conclusions</h3> PH-762 exhibits a promising therapeutic profile, with robust preclinical efficacy and favorable tolerability. The ongoing clinical trial will provide essential data on its safety, efficacy, and potential as a neoadjuvant immunotherapy for cutaneous malignancies, supporting its continued clinical advancement. Ethics Approval: Approved by Advarra Institutional Review Board (Approval Number: 00023875). <b>M. Maxwell:</b> A. Employment (full or part-time); Significant; Phio Pharmaceuticals. <b>L. Mahoney:</b> A. Employment (full or part-time); Significant; Phio Pharmaceuticals. <b>M. Spellman:</b> A. Employment (full or part-time); Significant; Phio Pharmaceuticals.