Abstract OT3-03-01: Phase I study of intratumoral administration of CF33-hNIS-antiPD-L1 (CHECKvacc) in patients with metastatic triple negative breast cancer
Authors: Yuan Yuan , Rand Jamie G. , Zhang Jianying , Kessler Jonathan , Modi Badri , Pillai Raju , Egelston Colt A. , Chaurasiya Shyambabu , Murga Mireya , Tang Aileen , Martinez Norma , Meisen Hans , Yamauchi Dave , Yost Susan E. , Chong Leslie , Seiz Amanda , Nixon Bonnie , Ede Nick , Waisman James , Stewart Daphne , Sedrak Mina S. , Fong Yuman 
Published: March 2023

Abstract
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.