Background The INTASYL™ compound PH-762 is designed to precisely silence PD-1 mRNA. INTASYL is a patented, self-delivering RNAi technology platform designed to impart specific properties to small interfering RNAs. PH-762’s unique structural and chemical modifications ensure an optimized cell and tissue uptake profile with intratumoral (IT) administration.

Immune checkpoint-targeted antibodies directed at PD-1 or PD-L1 block co-inhibitory receptors expressed by anti-tumor T cells, breaking immune tolerance against tumor cells and generating cancer immunity. Immunotherapy by IT injection aims to use the tumor as a ‘self-vaccine’. Local immune stimulation may induce robust priming of an anti-tumor immune response and generate abscopal tumor responses, mediated by circulating activated anti-tumor immune cells. Local delivery of immunotherapy minimizes systemic exposure and off-target toxicities and may decrease tumor size and improve surgical morbidity.

In vitro investigations have demonstrated efficient uptake of PH-762 by human T cells, silencing of PD-1 mRNA and subsequent protein reduction. Preclinical studies have shown that IT injections of murine-targeted PH-762 (mPH-762) can silence PD-1 mRNA in T cells within the tumor and increase the secretion of IFN-γ. mPH-762 was well tolerated at the maximum administered dose and treatment with mPH-762 provided robust and statistically significant inhibition of tumor growth.

Toxicokinetic studies conducted in marmoset monkeys demonstrated that PH-762, when administered intravenously at doses of up to 147 mg/kg, is well-tolerated. No cytokine-release associated cytokines were detected in the plasma of treated monkeys at this dose.

In the first-in-human clinical study of IT PH-762 (EudraCT 2021-002859-10), the product was well tolerated in 3 patients with metastatic melanoma.

Methods This open-label Phase 1 clinical study is designed to evaluate the safety and tolerability of neoadjuvant use of IT PH-762 in cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma, to determine the pharmacokinetic profile of PH-762 after IT injection, to observe pathologic and immunologic tumor responses, and to determine the recommended dose for development. Escalating dose concentrations of PH-762 (from 1.14 mg/mL through 22.00 mg/mL) are tested serially in cohorts of 3 patients each. Patients receive IT PH-762 once weekly, 4 times over a 3-week period prior to surgical excision 5 weeks after the initial injection. Following excision of the tumor, patients are followed for approximately 11 weeks. Tumor changes are evaluated per iRECIST criteria and pathological response. Immunological response in tumor tissue and blood samples are assessed as secondary endpoints.

Trial Registration clinicaltrials.gov (identifier: NCT06014086).

Ethics Approval This study was approved by Advarra Institutional Review Board; approval number 00023875.