Rand Jamie, Yamauchi Dave, Chaurasiya Shyambabu, Zhang Jianying, Deshpande Supriya, Chong Leslie, Seiz Amanda, Meisen Hans, Fong Yuman, Yuan Yuan
Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
Department of Radiology, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
Front Oncol. 2025 Aug 25;15:1565244. doi: 10.3389/fonc.2025.1565244. eCollection 2025.
Triple-negative breast cancer (TNBC) is clinically aggressive. CF33-hNIS-antiPDL1, an oncolytic orthopoxvirus, shows robust anti-cancer activity in TNBC xenografts in mice. CF33-hNIS-antiPDL1-infected tumor cells express functional human sodium iodide symporter (hNIS) and are visible by single-photon emission computed tomography (SPECT) or positron emission tomography (PET). We evaluated the ability of virus-encoded hNIS to track OV in mice using PET imaging and in a phase I study in TNBC patients using SPECT. The aim of this first-in-human study was to determine imageability and safety of intratumoral (IT) CF33-hNIS-antiPDL1 injections.
Imageability of CF33-hNIS-antiPDL1 was first assessed in mice bearing human xenografts. Virus or PBS-treated mice were imaged using a PET scanner. For the first-in-human trial, 9 patients were enrolled in this phase I, single-center, single-arm trial from October 2021 to August 2023. Key eligibility criteria included unresectable/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 received CF33-hNIS-antiPDL1 IT at 1 of 6 assigned dose levels (ranging from 1 × 105 PFU to 3 x 108 PFU) on days 1 and 15 of each 28-day cycle for 3 treatment cycles. SPECT whole-body imaging was performed using technetium-99 at cycle 1 day 8.
All mice treated with the virus showed clear PET signal from tumors whereas no signal was observed in PBS-treated mice. In the phase I study, 7 of 9 patients (78%) showed uptake at the injection site on SPECT imaging at C1D8. Five of 5 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 at injected lesions.
SPECT imaging successfully showed enhancement at the injected lesions in 78% of patients treated with CF33-hNIS-antiPDL1, even at low doses of the oncolytic virus (OV), suggesting local viral replication and hNIS expression. This is the first report of hNIS-based imaging to track oncolytic poxvirus replication in humans. This technology holds promise for noninvasive tracking of systemically administered OVs and other therapies.
https://www.clinicaltrials.gov/study/NCT05081492, identifier NCT05081492.
三阴性乳腺癌（TNBC）具有临床侵袭性。CF33-hNIS-antiPDL1是一种溶瘤正痘病毒，在小鼠TNBC异种移植瘤中显示出强大的抗癌活性。CF33-hNIS-antiPDL1感染的肿瘤细胞表达功能性人钠碘同向转运体（hNIS），可通过单光子发射计算机断层扫描（SPECT）或正电子发射断层扫描（PET）显影。我们使用PET成像评估了病毒编码的hNIS在小鼠中追踪溶瘤病毒（OV）的能力，并在一项针对TNBC患者的I期研究中使用SPECT进行了评估。这项首次人体研究的目的是确定瘤内（IT）注射CF33-hNIS-antiPDL1的显影性和安全性。
首先在荷人异种移植瘤的小鼠中评估CF33-hNIS-antiPDL1的显影性。使用PET扫描仪对病毒或PBS处理的小鼠进行成像。在首次人体试验中，从2021年10月至2023年8月，9名患者参加了这项I期单中心单臂试验。主要入选标准包括不可切除/转移性TNBC；至少接受过2种先前化疗方案后病情进展；东部肿瘤协作组（ECOG）体能状态0-2级；实体瘤疗效评价标准（RECIST）1.1可测量疾病；以及至少有一个适合重复IT注射的肿瘤。符合条件的患者在每个28天周期的第1天和第15天接受6个指定剂量水平（范围从1×10⁵ 空斑形成单位（PFU）到3×10⁸ PFU）之一的CF33-hNIS-antiPDL1 IT注射，共进行3个治疗周期。在第1周期第8天使用锝-99进行SPECT全身成像。
所有接受病毒治疗的小鼠肿瘤均显示清晰的PET信号，而PBS处理的小鼠未观察到信号。在I期研究中，9名患者中有7名（78%）在第1周期第8天的SPECT成像中注射部位有摄取。5名注射部位在转移性皮下结节、肌肉肿块或腋窝淋巴结的患者中有5名（100%），4名注射部位在融合性皮肤转移灶的患者中有2名（50%）在注射部位有摄取。
SPECT成像成功显示，在接受CF33-hNIS-antiPDL1治疗的患者中，78%的患者即使在低剂量溶瘤病毒（OV）情况下，注射部位也有强化，提示局部病毒复制和hNIS表达。这是基于hNIS成像追踪溶瘤痘病毒在人体中复制的首次报告。这项技术有望用于全身给药的OV和其他疗法的无创追踪。
https://www.clinicaltrials.gov/study/NCT05081492，标识符NCT05081492。
