{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T19:29:45Z","timestamp":1778614185690,"version":"3.51.4"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) achieves durable clinical benefit for patients from whom these cells can be derived in advanced metastatic melanoma but is limited in most solid tumors as a result of immune escape and exclusion. A tumor microenvironment (TME) priming strategy to improve the quantity and quality of TIL represents an important tactic to explore. Oncolytic viruses expressing immune stimulatory cytokines induce a potent inflammatory response that may enhance infiltration and activation of T cells. In this study, we examined the ability of an attenuated oncolytic vaccinia virus expressing IL15\/IL15R\u03b1 (vvDD-IL15\/R\u03b1) to enhance recovery of lavage T cells in peritoneal carcinomatosis (PC). We found that intraperitoneal (IP) vvDD-IL15\/R\u03b1 treatment of animals bearing PC resulted in a significant increase in cytotoxic function and memory formation in CD8<jats:sup>+<\/jats:sup>T cells in peritoneal fluid. Using tetramers for vaccinia virus B8R antigen and tumor rejection antigen p15E, we found that the expanded population of peritoneal CD8<jats:sup>+<\/jats:sup>T cells are specific for vaccinia or tumor with increased tumor-specificity over time, reinforced with viral clearance. Application of these vvDD-IL15\/R\u03b1 induced CD8<jats:sup>+<\/jats:sup>T cells in ACT of a lethal model of PC significantly increased survival. In addition, we found in patients with peritoneal metastases from various primary solid tumors that peritoneal T cells could be recovered but were exhausted with infrequent tumor-reactivity. If clinically translatable, vvDD-IL15\/R\u03b1<jats:italic>in vivo<\/jats:italic>priming would greatly expand the number of patients with advanced metastatic cancers responsive to T cell therapy.<\/jats:p>","DOI":"10.3389\/fimmu.2021.610042","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T15:51:00Z","timestamp":1613836260000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["In Vivo Priming of Peritoneal Tumor-Reactive Lymphocytes With a Potent Oncolytic Virus for Adoptive Cell Therapy"],"prefix":"10.3389","volume":"12","author":[{"given":"Esther","family":"Giehl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromichi","family":"Kosaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuqiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathilde","family":"Feist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Udai S.","family":"Kammula","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael T.","family":"Lotze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congrong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zong Sheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David L.","family":"Bartlett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI83871","article-title":"Cancer immunotherapy: harnessing the immune system to battle cancer","volume":"125","author":"Yang","year":"2015","journal-title":"J Clin Invest"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00555","article-title":"Oncolytic immunotherapy: Conceptual evolution, current strategies, and future perspectives","volume":"8","author":"Guo","year":"2017","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.2064","article-title":"Oncolytic viruses in cancer treatment: a review","volume":"3","author":"Lawler","year":"2017","journal-title":"JAMA Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30823-X","article-title":"CAR T cells: continuation in a revolution of immunotherapy","volume":"21","author":"Singh","year":"2020","journal-title":"Lancet Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e3181d32e74","article-title":"Cancer and inflammation: promise for biologic therapy","volume":"33","author":"Demaria","year":"2010","journal-title":"J Immunother"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz398","article-title":"Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis","volume":"30","author":"Dafni","year":"2019","journal-title":"Ann Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-018-2484-0","article-title":"Adoptive cellular therapies: the current landscape","volume":"474","author":"Rohaan","year":"2019","journal-title":"Virchows Arch"},{"key":"B8","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1016\/S1470-2045(17)30251-6","article-title":"Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study","volume":"18","author":"Chandran","year":"2017","journal-title":"Lancet Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-2722","article-title":"A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus-associated Epithelial Cancers","volume":"25","author":"Stevanovic","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxw014","article-title":"Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment","volume":"28","author":"Spranger","year":"2016","journal-title":"Int Immunol"},{"key":"B11","article-title":"Oncolytic Virus Promotes Tumor-Reactive Infiltrating Lymphocytes for Adoptive Cell Therapy. Oncolytic virus induces tumor-specific T Cells","volume-title":"Cancer Gene Ther: Nat","author":"Feist","year":"2020"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-431718","article-title":"IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors","volume":"121","author":"Cieri","year":"2013","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502337","article-title":"IL-15-Independent Maintenance of Tissue-Resident and Boosted Effector Memory CD8 T Cells","volume":"196","author":"Schenkel","year":"2016","journal-title":"J Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.58.3377","article-title":"Talimogene laherparepvec improves durable response rate in patients with advanced melanoma","volume":"33","author":"Andtbacka","year":"2015","journal-title":"J Clin Oncol"},{"key":"B15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40425-018-0495-7","article-title":"Vaccinia virus-mediated cancer immunotherapy: cancer vaccines and oncolytics","volume":"7","author":"Guo","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B16","doi-asserted-by":"publisher","first-page":"4682","DOI":"10.1038\/s41467-018-06954-z","article-title":"Modifying the cancer-immune set point using vaccinia virus expressing re-designed interleukin-2","volume":"9","author":"Liu","year":"2018","journal-title":"Nat Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.07.013","article-title":"Superagonist IL-15-Armed Oncolytic Virus Elicits Potent Antitumor Immunity and Therapy That Are Enhanced with PD-1 Blockade","volume":"26","author":"Kowalsky","year":"2018","journal-title":"Mol Ther"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz1863","article-title":"Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors","volume":"12","author":"Park","year":"2020","journal-title":"Sci Transl Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0009","article-title":"The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy","volume":"3","author":"Waldmann","year":"2015","journal-title":"Cancer Immunol Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0275","article-title":"High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor alpha fusion protein, in metastatic melanoma and colorectal cancer","volume":"8","author":"Bessard","year":"2009","journal-title":"Mol Cancer Ther"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0045","article-title":"Interleukin-15\/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells","volume":"68","author":"Epardaud","year":"2008","journal-title":"Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6536","article-title":"Transpresentation of interleukin-15 by IL-15\/IL-15R\u03b1 mRNA-engineered human dendritic cells boosts antitumoral natural killer cell activity","volume":"6","author":"Van den Bergh","year":"2015","journal-title":"Oncotarget"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081768","article-title":"Production of bioactive soluble interleukin-15 in complex with interleukin-15 receptor alpha from a conditionally-replicating oncolytic HSV-1","volume":"8","author":"Gaston","year":"2013","journal-title":"PLoS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-12-823757","article-title":"First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation","volume":"131","author":"Romee","year":"2018","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1016\/S1470-2045(18)30148-7","article-title":"ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial","volume":"19","author":"Wrangle","year":"2018","journal-title":"Lancet Oncol"},{"key":"B26","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.162.2.989","article-title":"High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy","volume":"162","author":"Zeh","year":"1999","journal-title":"J Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01904","article-title":"The Emerging Role of CD8","volume":"9","author":"Corgnac","year":"2018","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1016\/j.cell.2017.07.024","article-title":"Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade","volume":"170","author":"Wei","year":"2017","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-19-0398","article-title":"TCR Repertoire Diversity of Peripheral PD-1(+)CD8(+) T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non-Small Cell Lung Cancer","volume":"8","author":"Han","year":"2020","journal-title":"Cancer Immunol Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1007\/s10120-014-0440-5","article-title":"Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer","volume":"19","author":"Kim","year":"2016","journal-title":"Gastric Cancer"},{"key":"B31","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/cgt.2011.81","article-title":"The Immune Landscape of Cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1038\/cgt.2011.81","article-title":"Expressing human interleukin-15 from oncolytic vesicular stomatitis virus improves survival in a murine metastatic colon adenocarcinoma model through the enhancement of anti-tumor immunity","volume":"19","author":"Stephenson","year":"2012","journal-title":"Cancer Gene Ther"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.01.008","article-title":"Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells","volume":"21","author":"Engelhardt","year":"2012","journal-title":"Cancer Cell"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1348","article-title":"Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer","volume":"348","author":"Rizvi","year":"2015","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nature14404","article-title":"Melanoma-intrinsic \u03b2-catenin signalling prevents anti-tumour immunity","volume":"523","author":"Spranger","year":"2015","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2016-4363","article-title":"Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy","volume":"6","author":"Peng","year":"2016","journal-title":"Cancer Discov"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nature15520","article-title":"Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy","volume":"527","author":"Peng","year":"2015","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701041","article-title":"Metabolic Barriers to T Cell Function in Tumors","volume":"200","author":"Sugiura","year":"2018","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02103","article-title":"Oncolytic Viruses Partner With T-Cell Therapy for Solid Tumor Treatment","volume":"9","author":"Rosewell Shaw","year":"2018","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7470","article-title":"IL-15 superagonist\/IL-15RalphaSushi-Fc fusion complex (IL-15SA\/IL-15RalphaSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas","volume":"7","author":"Kim","year":"2016","journal-title":"Oncotarget"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0427-6","article-title":"PD-1 blockade-unresponsive human tumor-infiltrating CD8","volume":"18","author":"Kim","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1993.395","article-title":"Expression of a suppressive p15E-related epitope in colorectal and gastric cancer","volume":"68","author":"Foulds","year":"1993","journal-title":"Br J Cancer"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-17-0314","article-title":"Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus-Driven Production of a Bispecific T-cell Engager","volume":"6","author":"Wing","year":"2018","journal-title":"Cancer Immunol Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4967","article-title":"Adoptive cell transfer as personalized immunotherapy for human cancer","volume":"348","author":"Rosenberg","year":"2015","journal-title":"Science"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1219009","article-title":"Adoptively transferred natural killer cells maintain long-term antitumor activity by epigenetic imprinting and CD4","volume":"5","author":"Ni","year":"2016","journal-title":"Oncoimmunology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.cytogfr.2014.09.001","article-title":"Interleukin-15: new kid on the block for antitumor combination therapy","volume":"26","author":"Van den Bergh","year":"2015","journal-title":"Cytokine Growth Factor Rev"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3083.1996.d01-297.x","article-title":"Normal human immune peritoneal cells: subpopulations and functionalcharacteristics","volume":"44","author":"Kubicka","year":"1996","journal-title":"Scand J Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0244","article-title":"Phase I Study of Oncolytic Vaccinia Virus GL-ONC1 in Patients with Peritoneal Carcinomatosis","volume":"24","author":"Lauer","year":"2018","journal-title":"Clin Cancer Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2016.101","article-title":"Phase 1 study of intravenous oncolytic poxvirus (vvDD) in patients with advanced solid cancers","volume":"24","author":"Downs-Canner","year":"2016","journal-title":"Mol Ther"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2014.194","article-title":"First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity","volume":"23","author":"Zeh","year":"2015","journal-title":"Mol Ther"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.610042\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T15:50:55Z","timestamp":1697903455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.610042\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,18]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2021.610042"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.610042","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,18]]},"article-number":"610042"}}