Effect of UNO101 on tumor microenvironment in relapsed or refractory, unresectable, primary, or metastatic cutaneous and subcutaneous malignancies.
Authors: Amichay Meirovitz, David Greenberg, Mark D. Pegram, Jedidiah Monson
Journal: Journal of Clinical Oncology (2024)

e14575 Background: Nitric oxide (NO) is a ubiquitous, endogenously generated gas implicated in the homeostatic regulation of physiological processes, and NO is implicated in numerous pathological conditions. Preclinical studies evaluating the effect of high concentration exogenously administered NO demonstrated anti-cancer properties and suggested that it may serve as a potent tumoricidal agent. We have previously shown that treating mouse colon carcinoma (CT26) tumor-bearing mice with ultra-high concentrations of nitric oxide (UNO) upregulates innate and adaptive immune cells locally and systemically. Methods: Upon a signed written ICF, a single UNO101 dose of 25,000 parts per million (ppm), administered intratumorally over 5 minutes, was evaluated in relapsed or refractory, unresectable, primary, or metastatic cutaneous and subcutaneous malignancies. Subjects with an ECOG PS of 0–3, at least 3 months of life expectancy and tumor size of 4.5 mm minimum and 30 mm maximum length were eligible for enrollment. RECIST v1.1 and clinical physical examination by PI assessment was utilized to assess the rate of malignant tumor response. Toxicity was graded per NCI CTCAE v5.0. Results: In this first-in-human Phase 1 clinical trial, six subjects, 4F/2M were enrolled with a median age of 61.5 years, (range, 34–81) and ECOG PS reported as 0 or 1. Tumor types enrolled included breast (n=3), melanoma (n=1), and squamous cell carcinoma (n=2) with a median of 4 prior lines of therapy (range, 2–11) and a median of 4.7 years (range, 1.4–9.5) since time of diagnosis to study entry. One related SAE (not dose limiting) of hypoxia, Grade 4, was reported, which resulted in cessation of UNO101 treatment after 1:55 minutes. The other five administrations were completed successfully, with no further SAEs. Other reported drug related AEs were primarily Grade 1 that resolved/recovered without sequelae. Clinical immune blood biomarkers post UNO101 treatment demonstrated modulation of the tumor microenvironment by upregulating of cytotoxic T-cells (11.1%), T-central memory cells (190.6%) as a percent of total T-cells, and dendritic cells (231.4%) as a percentage of WBCs, from baseline to Day 21. Further, T-regulatory cells (38.0%) were downregulated as a percentage of total T-cells from baseline to Day 21. Based on available physical examination and caliper measurements, clinical presentation on Day 7 on two subjects, significant clinical responses were observed. Conclusions: To date,a single dose of UNO101 at 25,000 ppm is well tolerated, with biomarkers suggesting immune action within the tumor microenvironment, trending in a favorable direction on Day 21 in a heavily pre-treated population. Additional UNO101 single dose of 50,000 ppm, and possibly 100,000 ppm, will be further evaluated for safety/tolerability, impact on immune biomarkers, and preliminary efficacy. Clinical trial information: NCT05351502 .