{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:14:38Z","timestamp":1786119278563,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014533","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000}}],"reference-count":90,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["DE240100650"],"award-info":[{"award-number":["DE240100650"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["DP230100485"],"award-info":[{"award-number":["DP230100485"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German National Science Foundation","award":["EN-1119\/2-2"],"award-info":[{"award-number":["EN-1119\/2-2"]}]},{"name":"Wilhelm Sander Foundation Grant","award":["2018.058.01"],"award-info":[{"award-number":["2018.058.01"]}]},{"DOI":"10.13039\/501100010441","name":"Medical Faculty Heidelberg","doi-asserted-by":"crossref","award":["Stiftung f\u00fcr Krebsund Scharlachforschung"],"award-info":[{"award-number":["Stiftung f\u00fcr Krebsund Scharlachforschung"]}],"id":[{"id":"10.13039\/501100010441","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100010449","name":"Nationales Centrum f\u00fcr Tumorerkrankungen Heidelberg","doi-asserted-by":"publisher","award":["Postdoctoral Fellowship from the Heidelberg School of Oncology"],"award-info":[{"award-number":["Postdoctoral Fellowship from the Heidelberg School of Oncology"]}],"id":[{"id":"10.13039\/501100010449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Immunotherapies have become a transformative therapeutic strategy for many cancer types in recent years. Bispecific T-cell engagers (BiTEs) are one promising immunotherapy that enhances cellular antitumour immunity by redirecting T cells towards cancer cells. Recent evidence suggests that BiTE efficacy can be augmented by encoding BiTEs in oncolytic measles virus vectors (MV-BiTE). Infection of cancer cells with MV-BiTE causes the local production of BiTEs and has shown safety and efficacy in murine tumour models. However, whether the observed efficacy of this treatment will translate to a heterogeneous human population is unknown. In this work, we generate an\n                    <jats:italic>in silico<\/jats:italic>\n                    clinical trial of MV-BiTE therapy using a system of ordinary differential equations. We capture potential heterogeneity of individual patients using variability in\n                    <jats:italic>in vivo<\/jats:italic>\n                    tumour volume and change in baseline (%) measurements from a Phase II clinical trial. In lieu of human MV-BiTE data, we use the oncolytic virus talimogene laherparepvec (T-VEC) as a surrogate oncolytic virus carrying an immunostimulatory payload. Our predictions imply that the main drivers of heterogeneity are the underlying effector T cell killing rate and BiTE pharmacokinetics. Furthermore, we find that if individuals are classified as non-responders to the Phase II T-VEC clinical protocol, they may respond to more frequent administration of lower dosages. This work highlights how\n                    <jats:italic>in silico<\/jats:italic>\n                    clinical trials can provide predictions for novel therapeutics to generate hypotheses and guide the design of treatment schedules for clinical translation.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014533","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:53:24Z","timestamp":1785434004000},"page":"e1014533","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["In silico clinical trials of BiTE expression by oncolytic viruses reveal the impact of patient heterogeneity on dosage protocol"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9103-7092","authenticated-orcid":true,"given":"Adrianne L.","family":"Jenner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-2214","authenticated-orcid":true,"given":"Robyn P.","family":"Araujo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2635-1426","authenticated-orcid":true,"given":"Noa L.","family":"Levi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Ungerechts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine E.","family":"Engeland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes P. W.","family":"Heidbuechel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"pcbi.1014533.ref001","doi-asserted-by":"crossref","DOI":"10.3747\/co.27.5223","article-title":"A review of cancer immunotherapy: from the past, to the present, to the future","volume":"27","author":"K Esfahani","year":"2020","journal-title":"Curr Oncol"},{"issue":"3","key":"pcbi.1014533.ref002","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/icb.2014.93","article-title":"Bispecific T-cell engagers for cancer immunotherapy","volume":"93","author":"AM Huehls","year":"2015","journal-title":"Immunol Cell Biol"},{"issue":"1","key":"pcbi.1014533.ref003","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s12964-023-01430-8","article-title":"New immunotherapy approaches for colorectal cancer: focusing on CAR-T cell, BiTE, and oncolytic viruses","volume":"22","author":"A Kamrani","year":"2024","journal-title":"Cell Commun Signal"},{"issue":"1","key":"pcbi.1014533.ref004","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13045-021-01084-4","article-title":"Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies","volume":"14","author":"Z Tian","year":"2021","journal-title":"J Hematol Oncol"},{"key":"pcbi.1014533.ref005","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ymeth.2018.10.026","article-title":"Bispecific T-cell engagers: towards understanding variables influencing the in vitro potency and tumor selectivity and their modulation to enhance their efficacy and safety","volume":"154","author":"D Ellerman","year":"2019","journal-title":"Methods"},{"issue":"17","key":"pcbi.1014533.ref006","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1182\/blood-2013-11-492231","article-title":"Antibody-modified T cells: CARs take the front seat for hematologic malignancies","volume":"123","author":"MV Maus","year":"2014","journal-title":"Blood"},{"issue":"10","key":"pcbi.1014533.ref007","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1016\/S1470-2045(25)00480-2","article-title":"Safety and activity of tarlatamab in combination with a PD-L1 inhibitor as first-line maintenance therapy after chemo-immunotherapy in patients with extensive-stage small-cell lung cancer (DeLLphi-303): a multicentre, non-randomised, phase 1b study","volume":"26","author":"KG Paulson","year":"2025","journal-title":"Lancet Oncol"},{"issue":"4","key":"pcbi.1014533.ref008","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1056\/NEJMoa2502099","article-title":"Tarlatamab in small-cell lung cancer after platinum-based chemotherapy","volume":"393","author":"G Mountzios","year":"2025","journal-title":"N Engl J Med"},{"key":"pcbi.1014533.ref009","doi-asserted-by":"crossref","unstructured":"Stein MN, Vinceneux A, Robbrecht D, Doger B, Autio KA, Schweizer MT, et al. 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