PD-1–directed intratumoral immunotherapy for cutaneous carcinomas: Interim results from an ongoing study of INTASYL PH-762.

9591 Background: 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. PH-762 is an INTASYL compound designed to precisely silence PD-1 mRNA. INTASYL is a patented, self-delivering RNAi technology 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. Local delivery of immunotherapy minimizes systemic exposure and off-target toxicities and may decrease tumor size and improve surgical morbidity. The efficient uptake of PH-762 by human T cells, silencing of PD-1 mRNA and subsequent protein reduction has been demonstrated preclinically. Murine-targeted PH-762 (mPH-762) injections are able to silence PD-1 mRNA in T cells within the murine tumor and increase the secretion of IFN-γ. Methods: This open-label Phase 1 clinical study (NCT 06014086) 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, which occurs 5 weeks after the initial injection. Tumor changes are evaluated per iRECIST criteria and pathological response. Results: Seven patients in two dose cohorts have received IT PH-762 (1.14 or 2.39 mg/mL). No dose-limiting toxicities or serious adverse events have been reported. Pathologic response was reported following surgical excision of the tumor (or tumor site). Of the 6 patients with SCC, 2 had complete response, 2 had partial response (1 near complete with <10% viable tumor), and 2 were non-responders. One patient with metastatic melanoma had no response. Conclusions: IT PH-762 has been well tolerated, with no evident safety signals or reported systemic or off-target toxicities, and dose escalation has resumed per protocol. Clinical and histologic evidence of tumor response is encouraging. PH-762 may decrease tumor bulk or provide a non-surgical alternative in specific circumstances, while minimizing systemic exposure and off-target toxicities. Clinical outcomes, coupled with pharmacokinetic and immunologic response data will inform continued clinical development of PH-762. Clinical trial information: 06014086 .