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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.

Background: Despite recent FDA approvals of immune checkpoint inhibitor pembrolizumab and drug-antibody conjugate in the treatment of metastatic triple negative breast cancer (mTNBC), the overall survival benefit of these therapies remains modest. Oncolytic virotherapy (OV) utilizes genetically modified viruses to infect and kill cancer cells while sparing healthy cells. CF33-hNIS-anti-PD-L1 (CHECKvacc) is a novel chimeric orthopoxvirus with robust anti-cancer activity in TNBC xenografts. Cells infected with CHECKvacc were shown to express functional human sodium-iodide symporter (hNIS) and anti-PD-L1 proteins. hNIS gene transfer allows tracking of virus by 99mTc single-photon emission computed tomography (SPECT). Our preliminary animal studies demonstrated that tumor cells infected with CHECKvacc successfully secrete functional hNIS and anti-PD-L1. CHECKvacc administered by intratumoral injection appears safe and is generally well-tolerated. CHECKvacc detects and effectively kills TNBC at doses several magnitudes lower than other OVs in xenograft models. Methods: This study is a first-in-human phase I, single center, single arm clinical trial evaluating the safety and tolerability of CHECKvacc intratumoral injection in patients with mTNBC. Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on at least 2 prior chemotherapies including an immune checkpoint inhibitor-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease; and at least one tumor amenable to repeated intratumoral injections. Eligible patients receive CHECKvacc intratumorally at one of 8 assigned dose levels (1 × 105 PFU, 3 × 105 PFU, 1 × 106 PFU, 3× 106 PFU, 1 × 107 PFU, 3 × 107 PFU, 1 × 108 PFU, 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 CHECKvacc by CTCAE v5.0. Secondary objectives are to determine optimal biological dose, recommended phase II dose (RP2D), and response rate by RECIST1.1. The first 3 subjects of dose level 1 were enrolled sequentially for safety monitoring. Once the initial 3 subjects were treated sequentially, the study followed the Phase I Queue 3+3 (IQ 3+3) design which expands a dose level up to 8 subjects after a single DLT has been observed. Enrollment to the final RP2D may be expanded to include up to 12 patients for efficacy assessment. The estimated targeted accrual is 33 patients (minimum) to 78 patients (maximum). Correlative aims include assessing viral kinetics, viral plaque assay, 99mTc SPECT imaging for virus tracking, peripheral blood and tumor tissue for antiviral immune activation, and tumor microenvironment changes in association with response to therapy. Results: From October 2021 to June 2022, 6 patients were enrolled and received at least 1 dose of CHECKvacc injection at dose level 1 (1 x 10^5 pfu) and 2 (3 x 10^5 pfu). The intratumoral CHECKVacc injections were well tolerated. No DLTs were observed. No treatment emergent AEs (TEAEs) have been reported for the 6 patients so far. 99mTc SPECT imaging for virus tracking is on-going. Baseline and on treatment tumor biopsies were submitted for spatial immune profiling. Peripheral blood at baseline, on treatment and EOT were subjected for flow cytometry analysis. Conclusion: CF33hNIS-antiPD-L1 administered by intratumoral injection in patients with mTNBC is safe and well tolerated at the dose levels tested. Clinical trial information: NCT05081492 Citation Format: Yuan Yuan, Jamie G. Rand, Jianying Zhang, Jonathan Kessler, Badri Modi, Raju Pillai, Colt A. Egelston, Shyambabu Chaurasiya, Mireya Murga, Aileen Tang, Norma Martinez, Hans Meisen, Dave Yamauchi, Susan E. Yost, Leslie Chong, Amanda Seiz, Bonnie Nixon, Nick Ede, James Waisman, Daphne Stewart, Mina S. Sedrak, Yuman Fong. Phase I study of intratumoral administration of CF33-hNIS-antiPD-L1 (CHECKvacc) in patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-03-01.

e13070 Background: Despite recent FDA approval of immune checkpoint inhibitor pembrolizumab and drug-antibody conjugate in the treatment of metastatic triple negative breast cancer (mTNBC), the overall survival benefit of these therapies remains modest. Oncolytic virotherapy (OV) utilizes genetically modified viruses to infect and kill cancer cells while sparing healthy cells. CF33-hNIS-anti-PD-L1 (CHECKvacc) is a novel chimeric orthopoxvirus with robust anti-cancer activity in TNBC xenografts. Cells infected with CHECKvacc were shown to express functional human sodium-iodide symporter (hNIS) and anti-PD-L1 proteins. hNIS gene transfer allows tracking of virus by 99mTc single-photon emission computed tomography (SPECT). Our preliminary animal studies demonstrated that tumor cells infected with CHECKvacc successfully secrete functional hNIS and anti-PD-L1. CHECKvacc is safe and well-tolerated, and detects and effectively kills TNBC at doses several magnitudes lower than other OVs in xenograft models. Methods: This study is a first-in-human (FIH) phase I, single center, single arm clinical trial evaluating the safety and tolerability of CHECKvacc intratumoral injection in patients with mTNBC. Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on at least 2 prior chemotherapies including immune checkpoint inhibitor-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease; and at least one tumor amenable to repeated intratumoral injections. Eligible patients receive CHECKvacc intratumorally at one of 8 assigned dose levels (1 × 105 PFU, 3 × 105 PFU, 1 × 106 PFU, 3× 106 PFU, 1 × 107 PFU, 3 × 107 PFU, 1 × 108 PFU, 3 x 108 PFU) on Days 1 and 15 of each 28-day cycle for a total of 3 cycles of treatment. Primary objectives are to evaluate the safety and tolerability of CHECKvacc (DLTs and other toxicities by CTCAE v5.0). Secondary objectives are to determine optimal biological dose (OBD), recommended phase II dose (RP2D), and response rate by RECIST1.1. Results: The first 3 subjects of dose level 1 will be enrolled sequentially for safety monitoring. Once the initial 3 subjects are treated sequentially, the study will follow the Phase I Queue 3+3 (IQ 3+3) design which expands a dose level up to 8 subjects after a single DLT has been observed. Enrollment to the final RP2D may be expanded to include up to 12 patients for efficacy assessment. The estimated targeted accrual is 33 patients (minimum) to 78 patients (maximum). Correlative aims include assessing viral kinetics, viral plaque assay, 99mTc SPECT imaging for virus tracking, peripheral blood and tumor tissue for antiviral immune activation, and tumor microenvironment changes in association with response to therapy. Conclusions: This FIH trial of CF33-hNIS-antiPD-L1 intratumoral injection in patients with mTNBC is currently underway. Clinical trial information: NCT05081492.