{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:19:00Z","timestamp":1789676340797,"version":"4.0.1"},"reference-count":50,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:00:00Z","timestamp":1706659200000},"content-version":"unspecified","delay-in-days":30,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021954","name":"Tour de Cure","doi-asserted-by":"publisher","award":["RSP-206-2020"],"award-info":[{"award-number":["RSP-206-2020"]}],"id":[{"id":"10.13039\/501100021954","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Australian Government Research Training Program Scholarship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,1,11]]},"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Skin cancers, particularly keratinocyte cancers, are the most commonly diagnosed tumors. Although surgery is often effective in early-stage disease, skin tumors are not always easily accessible, can reoccur and have the ability to metastasize. More recently, immunotherapies, including intravenously administered checkpoint inhibitors, have been shown to control some skin cancers, but with off-target toxicities when used in combination. Our study investigated whether peritumoral administration of an antibody combination targeting PD-1, 4-1BB (CD137) and VISTA might control skin tumors and lead to circulating antitumor immunity without off-target toxicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The efficacy of combination immunotherapy administered peritumorally or intravenously was tested using transplantable tumor models injected into mouse ears (primary tumors) or subcutaneously in flank skin (secondary tumors). Changes to the tumor microenvironment were tracked using flow cytometry while tumor-specific, CD8 T cells were identified through enzyme-linked immunospot (ELISPOT) assays. Off-target toxicity of the combination immunotherapy was assessed via serum alanine aminotransferase ELISA and histological analysis of liver sections.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The data showed that local administration of antibody therapy eliminated syngeneic murine tumors transplanted in the ear skin at a lower dose than required intravenously, and without measured hepatic toxicity. Tumor elimination was dependent on CD8 T cells and was associated with an increased percentage of CD8 T cells expressing granzyme B, KLRG1 and Eomes, and a decreased population of CD4 T cells including CD4<jats:sup>+<\/jats:sup>FoxP3<jats:sup>+<\/jats:sup> cells in the treated tumor microenvironment. Importantly, untreated, distal tumors regressed following antibody treatment of a primary tumor, and immune memory prevented growth of subcutaneous flank tumors administered 50 days after regression of a primary tumor.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Together, these data suggest that peritumoral immunotherapy for skin tumors offers advantages over conventional intravenous delivery, allowing antibody dose sparing, improved safety and inducing long-term systemic memory. Future clinical trials of immunotherapy for primary skin cancer should focus on peritumoral delivery of combinations of immune checkpoint antibodies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2023-007960","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T12:25:44Z","timestamp":1706703944000},"page":"e007960","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Peritumoral administration of immunomodulatory antibodies as a triple combination suppresses skin tumor growth without systemic toxicity"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9628-0200","authenticated-orcid":false,"given":"Quentin G","family":"Wright","sequence":"first","affiliation":[{"name":"Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7153-856X","authenticated-orcid":false,"given":"Debottam","family":"Sinha","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9618-6940","authenticated-orcid":false,"given":"James W","family":"Wells","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian H","family":"Frazer","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2671-7408","authenticated-orcid":false,"given":"Jazmina L","family":"Gonzalez Cruz","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4078-5653","authenticated-orcid":false,"given":"Graham Robert","family":"Leggatt","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"2025100313354881000_12.1.e007960.1","doi-asserted-by":"crossref","DOI":"10.1016\/j.tranon.2022.101557","article-title":"Unravelling the landscape of skin cancer through single-cell transcriptomics","volume":"27","author":"Srivastava","year":"2023","journal-title":"Transl Oncol"},{"key":"2025100313354881000_12.1.e007960.2","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1002\/cam4.4046","article-title":"Global, regional and national incidence, mortality and disability\u2010adjusted life\u2010years of skin cancers and trend analysis from 1990 to 2019: an analysis of the global burden of disease study 2019","volume":"10","author":"Zhang","year":"2021","journal-title":"Cancer Medicine"},{"key":"2025100313354881000_12.1.e007960.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2017.08.059"},{"key":"2025100313354881000_12.1.e007960.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200103293441306"},{"key":"2025100313354881000_12.1.e007960.5","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1001\/jamadermatol.2013.2139","article-title":"Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study","volume":"149","author":"Schmults","year":"2013","journal-title":"JAMA Dermatol"},{"key":"2025100313354881000_12.1.e007960.6","unstructured":"Banerjee S , Kaunelis D . 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