Clinical study of intratumoral PH-762 targeting PD-1 for cutaneous carcinomas

Summary: Abstract Body: Immune checkpoint 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. The INTASYL™ compound PH-762 is designed to silence PD-1 mRNA within the T cells, providing an alternative to an antibody blockade. Structural and chemical modifications ensure an optimized cell and tissue uptake profile with intratumoral (IT) administration. Preclinical pharmacology studies of PH-762 in syngeneic tumor models demonstrated potent in vitro silencing of PD-1 associated with T cell activation, and robust, dose-dependent in vivo inhibition of tumor growth. In this open-label Phase 1b clinical study (NCT 06014086), escalating dose concentrations of PH-762 (from 1.14 mg/mL through 22.00 mg/mL) are tested serially in cohorts of 3 patients with cutaneous squamous cell carcinoma (SCC), melanoma, or Merkel cell carcinoma (MCC). Patients receive 4 doses of IT PH-762 weekly over a 3-week period prior to surgical excision 2 weeks later. Tumor changes are evaluated per iRECIST criteria and pathological response. Across the initial 2 cohorts, seven patients received IT PH-762 (1.14 or 2.39 mg/mL). No dose-limiting toxicities or serious adverse events were 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 was near complete with <10% viable tumor), and 2 were non-responders. One patient with metastatic melanoma had no response. IT PH-762 has been well tolerated, with no evident safety signals or reported systemic or off-target toxicities. 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. Mary C. Spellman¹, Katharine Furst², Linda Mahoney³ 1. Panclarity LLC, San Francisco, CA, United States. 2. Prosoft Clinical, Chesterbrook, PA, United States. 3. Phio Pharmaceuticals, Marlborough, MA, United States. Clinical Research: Interventional Research