{"doi":"10.1016/j.omton.2024.200852","title":"Smoldering oncolysis by foamy virus carrying CD19 as a CAR target escapes CAR T detection by genomic modification","abstract":"Chimeric antigen receptor (CAR) T cells have had limited success against solid tumors. Here, we used an oncolytic foamy virus (oFV) to display a model CAR target antigen (CD19) on tumors in combination with anti-CD19 CAR T cells. We generated oFV-Δbel2 and oFV-bel2 vectors to test the efficiency and stability of viral/CD19 spread. While both viruses conferred equal CAR T killing in vitro, the oFV-Δbel2 virus acquired G-to-A mutations, whereas oFV-bel2 virus had genome deletions. In subcutaneous tumor models in vivo, CAR T cells led to a significant decrease in oFV-specific bioluminescence, confirming clearance of oFV-infected tumor cells. However, the most effective therapy was with high-dose oFV in the absence of CAR T cells, indicating that CAR T clearance of oFV was detrimental. Moreover, in tumors that escaped CAR T cell treatment, resurgent virus contained deletions within the oFV-CD19 transgene, allowing the virus to escape CAR T elimination. Therefore, oFV represents a slow smoldering type of oncolytic virus, whose chronic spread through tumors generates anti-tumor therapy, which is abolished by CAR T therapy. These results suggest that further development of this oncolytic platform, with additional immunotherapeutic arming, may allow for an effective combination of chronic oncolysis. Chimeric antigen receptor (CAR) T cells have had limited success against solid tumors. Here, we used an oncolytic foamy virus (oFV) to display a model CAR target antigen (CD19) on tumors in combination with anti-CD19 CAR T cells. We generated oFV-Δbel2 and oFV-bel2 vectors to test the efficiency and stability of viral/CD19 spread. While both viruses conferred equal CAR T killing in vitro, the oFV-Δbel2 virus acquired G-to-A mutations, whereas oFV-bel2 virus had genome deletions. In subcutaneous tumor models in vivo, CAR T cells led to a significant decrease in oFV-specific bioluminescence, confirming clearance of oFV-infected tumor cells. However, the most effective therapy was with high-dose oFV in the absence of CAR T cells, indicating that CAR T clearance of oFV was detrimental. Moreover, in tumors that escaped CAR T cell treatment, resurgent virus contained deletions within the oFV-CD19 transgene, allowing the virus to escape CAR T elimination. Therefore, oFV represents a slow smoldering type of oncolytic virus, whose chronic spread through tumors generates anti-tumor therapy, which is abolished by CAR T therapy. These results suggest that further development of this oncolytic platform, with additional immunotherapeutic arming, may allow for an effective combination of chronic oncolysis.","journal":"Molecular Therapy Oncology","year":2024,"id":448994,"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":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":726047,"name":"Karol Budzik","orcid":"0000-0002-4112-9914","position":1,"is_corresponding":false},{"id":1268808,"name":"Talia Fernandez Carrasco","orcid":null,"position":2,"is_corresponding":false},{"id":1268809,"name":"Landon Ebbert","orcid":null,"position":3,"is_corresponding":false},{"id":250275,"name":"Jill Thompson","orcid":"0000-0001-5005-7257","position":4,"is_corresponding":false},{"id":504110,"name":"Rebecca A. Nace","orcid":null,"position":5,"is_corresponding":false},{"id":1171014,"name":"Benjamin Kendall","orcid":null,"position":6,"is_corresponding":false},{"id":283670,"name":"Rosa María Díaz","orcid":null,"position":7,"is_corresponding":false},{"id":282366,"name":"Stephen J. Russell","orcid":"0000-0002-0799-6432","position":8,"is_corresponding":false},{"id":271089,"name":"Richard G. Vile","orcid":"0000-0003-2192-9372","position":9,"is_corresponding":false},{"id":272859,"name":"Jason M. Tonne","orcid":null,"position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T02:02:16.291892Z","pmid":"39220111","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":[]}