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When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, studies in hamsters have shown a 100% complete response rate when animals were treated with oncolytic adenovirus coding for TNFa and IL-2 (Ad5\/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) and TIL therapy. In humans, one caveat with oncolytic virus therapy is that intratumoral injection has been traditionally preferred over systemic administration, for achieving sufficient virus concentrations in tumors, especially when neutralizing antibodies emerge. We have previously shown that 5\/3 chimeric oncolytic adenovirus can bind to human lymphocytes for avoidance of neutralization. In this study, we hypothesized that incubation of oncolytic adenovirus (TILT-123) with TILs prior to systemic injection would allow delivery of virus to tumors. This approach would deliver both components in one self-amplifying product. TILs would help deliver TILT-123, whose replication will recruit more TILs and increase their cytotoxicity. In vitro, TILT-123 was seen binding efficiently to lymphocytes, supporting the idea of dual administration. We show in vivo in different models that virus could be delivered to tumors with TILs as carriers.<\/jats:p>","DOI":"10.3390\/cells10050978","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T13:59:14Z","timestamp":1619099954000},"page":"978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Systemic Delivery of Oncolytic Adenovirus to Tumors Using Tumor-Infiltrating Lymphocytes as Carriers"],"prefix":"10.3390","volume":"10","author":[{"given":"Joao","family":"Santos","sequence":"first","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"},{"name":"TILT Biotherapeutics Ltd., 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-2146","authenticated-orcid":false,"given":"Camilla","family":"Heini\u00f6","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2614-3942","authenticated-orcid":false,"given":"Dafne","family":"Quixabeira","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadia","family":"Zafar","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Clubb","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"},{"name":"TILT Biotherapeutics Ltd., 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santeri","family":"Pakola","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6684-3666","authenticated-orcid":false,"given":"Victor","family":"Cervera-Carrascon","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"},{"name":"TILT Biotherapeutics Ltd., 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riikka","family":"Havunen","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"},{"name":"TILT Biotherapeutics Ltd., 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kanerva","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"},{"name":"Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7103-8530","authenticated-orcid":false,"given":"Akseli","family":"Hemminki","sequence":"additional","affiliation":[{"name":"Cancer Gene Therapy Group, Faculty of Medicine, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland"},{"name":"TILT Biotherapeutics Ltd., 00290 Helsinki, Finland"},{"name":"Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1126\/science.1076514","article-title":"Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes","volume":"298","author":"Dudley","year":"2002","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s40425-018-0391-1","article-title":"Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: A viable treatment option","volume":"6","author":"Rohaan","year":"2018","journal-title":"J. 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