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Background: CF33-hNIS-anti-PD-L1 is a novel chimeric orthopoxvirus shown to have anti-cancer activity in triple negative breast cancer (TNBC) xenografts. For clinical tracking of the oncolytic virus (OV), human sodium iodide symporter (hNIS) transgene was inserted into the virus. hNIS gene expression allows cells to take up iodine and be visible by non-invasive imaging techniques. Animal studies showed that tumor cells infected with CF33-hNIS-anti-PD-L1 express functional hNIS and are visible by single-photon emission computed tomography (SPECT) or positron emission tomography (PET). The current report describes imaging results from an ongoing first-in-human trial. Methods: This is a phase I, single center, single arm clinical trial evaluating the safety and tolerability of CF33-hNIS-anti-PD-L1 intratumoral (IT) injections in patients with metastatic TNBC. Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on at least 2 prior chemotherapies; ECOG 0-2; RECIST 1.1 measurable disease; and at least one tumor amenable to repeated IT injections. Eligible patients receive CF33-hNIS-anti-PD-L1 IT at 1 of 8 assigned dose levels (from 1 × 105 PFU to 3 x 108 PFU) on Days 1 and 15 of each 28-day cycle for a total of 3 cycles of treatment. The primary objective is to evaluate the safety and tolerability of CF33-hNIS-anti-PD-L1. Secondary objectives are to determine optimal biological dose, recommended phase II dose, and response rates. Exploratory objectives include assessing feasibility of non-invasive hNIS imaging as a method of tracking viral infection and replication. SPECT whole body imaging was performed at Cycle 1 Day 8 (C1D8). Results: From October 2021 to October 2022, 8 patients were enrolled in this ongoing study and received at least 1 dose of CF33-hNIS-anti-PD-L1 injection at one of the first 3 dose levels (1 x 105, 3 x 105, or 1 x 106 PFU). All 8 patients underwent SPECT imaging at C1D8 with 6/8 patients (75%) having uptake at the site of injection on the SPECT imaging study. Four of 4 patients (100%) with injection sites at metastatic subcutaneous nodules, intramuscular masses, or axillary lymph nodes and 2/4 patients (50%) with injection sites at matted dermal metastatic lesions had uptake on SPECT. Conclusion: SPECT imaging successfully showed enhancement at the injected lesions in 75% of patients treated with CF33-hNIS-anti-PD-L1, even at current low doses, suggesting local viral replication and hNIS expression. Further analysis will evaluate the correlation of SPECT imaging results with pathologic immune cell infiltrate, viral staining, and tumor response. This is the first known report of hNIS-based imaging to track oncolytic poxvirus replication in humans and gives promise that this technology may be used for noninvasive tracking of systemically administered OV and other therapies. Citation Format: Jamie Green Rand, Dave Yamauchi, Shyambabu Chaurasiya, Jianying Zhang, Raju Pillai, Colt Egelston, Jonathan Kessler, Badri Modi, Leslie Chong, Amanda Seiz, Giovanni Selvaggi, Nick Ede, Mireya Murga, Norma Martinez, Wichanee Borisuthirattana, Hans Meisen, Susan Yost, James Waisman, Daphne Stewart, Joanne Mortimer, Yuman Fong, Yuan Yuan. hNIS imaging data from a first-in-human trial of the oncolytic virus CF33-hNIS-antiPD-L1 in patients with triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6788.