{"doi":"10.3389/fonc.2021.821838","title":"Interventional Optical Imaging-Monitored Synergistic Effect of Radio-Frequency Hyperthermia and Oncolytic Immunotherapy","abstract":"Purpose To develop a new interventional oncology technique using indocyanine green (ICG)-based interventional optical imaging (OI) to monitor the synergistic effect of radiofrequency hyperthermia (RFH)-enhanced oncolytic immunotherapy. Materials and Methods This study included (1) optimization of ICG dose and detection time-window for intracellular uptake by VX2 tumor cells; (2) in-vitro confirmation of capability of using ICG-based OI to assess efficacy of RFH-enhanced oncolytic therapy (LTX-401) for VX2 cells; and (3) in-vivo validation of the interventional OI-monitored, intratumoral RFH-enhanced oncolytic immunotherapy using rabbit models with orthotopic liver VX2 tumors. Both in-vitro and in-vivo experiments were divided into four study groups (n=6/group) with different treatments: (1) combination therapy of RFH+LTX-401; (2) RFH alone at 42°C for 30 min; (3) oncolytic therapy with LTX-401; and (4) control with saline. For in-vivo validation, orthotopic hepatic VX2 tumors were treated using a new multi-functional perfusion-thermal radiofrequency ablation electrode, which enabled simultaneous delivery of both LTX-401 and RFH within the tumor and at the tumor margins. Results In in-vitro experiments, taking up of ICG by VX2 cells was linearly increased from 0 μg/mL to 100 μg/mL, while ICG-signal intensity (SI) reached the peak at 24 hours. MTS assay and apoptosis analysis demonstrated the lowest cell viability and highest apoptosis in combination therapy, compared to three monotherapies ( P <0.005). In in-vivo experiments, ultrasound imaging detected the smallest relative tumor volume for the combination therapy, compared to other monotherapies ( P <0.005). In both in-vitro and in-vivo experiments, ICG-based interventional optical imaging detected a significantly decreased SI in combination therapy ( P <0.005), which was confirmed by the “gold standard” optical/X-ray imaging ( P <0.05). Pathologic/laboratory examinations further confirmed the significantly decreased cell proliferation with Ki-67 staining, significantly increased apoptotic index with TUNEL assay, and significantly increased quantities of CD8 and CD80 positive cells with immunostaining in the combination therapy group, compared to other three control groups ( P <0.005). Conclusions We present a new interventional oncology technique, interventional optical imaging-monitored RFH-enhanced oncolytic immunotherapy, which may open new avenues to effectively manage those patients with larger, irregular and unresectable malignancies, not only in liver but also the possibility in other organs.","journal":"Frontiers in Oncology","year":2022,"id":284542,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":790154,"name":"Feng Zhang","orcid":"0000-0003-1098-4712","position":1,"is_corresponding":false},{"id":419994,"name":"Wayne L. Monsky","orcid":"0000-0003-0694-6502","position":2,"is_corresponding":false},{"id":747045,"name":"Hongxiu Ji","orcid":"0000-0003-2050-4700","position":3,"is_corresponding":false},{"id":962310,"name":"Weizhu Yang","orcid":"0000-0001-8470-1709","position":4,"is_corresponding":false},{"id":452494,"name":"Xiaoming Yang","orcid":"0000-0002-4076-3569","position":5,"is_corresponding":false},{"id":755998,"name":"Hui Zheng","orcid":"0000-0002-0622-4430","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T00:29:36.828109Z","pmid":"35141157","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}