{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T22:37:08Z","timestamp":1790030228095,"version":"4.0.1"},"reference-count":12,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The investigational antigen\u2010specific immunotherapy mRNA\u20104359 is a lipid nanoparticle\u2013encapsulated mRNA\u2010based immunotherapy that encodes for the immunogenic indoleamine 2,3\u2010dioxygenase (IDO) and programmed death\u2010ligand 1 (PD\u2010L1) antigens. An ongoing first\u2010in\u2010human (FIH) phase 1\/2 clinical trial (NCT05533697) will evaluate the safety and antitumor activity of mRNA\u20104359 when administered alone and in combination with the anti\u2013programmed death\u20101 agent pembrolizumab in participants with advanced solid tumors. The current analysis applied a novel immunostimulatory\/immunodynamic (IS\/ID) modeling approach to determine a plausible starting dose of mRNA\u20104359 for the FIH trial. The model used for the FIH dose prediction was calibrated to previously published clinical trial data obtained for an immunomodulatory peptide\u2010based vaccine activating IDO\u2010 and PD\u2010L1\u2013specific T cells in patients with metastatic melanoma. The analysis found that a 180\u2009\u03bcg dose of mRNA\u20104359 would possibly elicit a T\u2010cell response similar to a 200\u2009\u03bcg dose of the peptide\u2010based vaccine with a range of 45\u2013360\u2009\u03bcg, assuming a potential 4\u2010fold higher to 2\u2010fold lower efficiency (the ability to elicit IFN\u2010\u03b3 secreting T cells, indicative of cytotoxic potential). Model simulations further predicted that a 15\u2010cycle every 3 weeks regimen of mRNA\u20104359 could be expected to provide longer responses than other feasible simulated regimens. Finally, the IS\/ID modeling analysis determined that a 100\u2009\u03bcg dose of mRNA\u20104359 would be the most appropriate starting dose for FIH trials. The described approach represents a unique application of IS\/ID modeling to determine a therapeutically relevant FIH starting dose in the absence of supporting preclinical animal data.<\/jats:p>","DOI":"10.1002\/psp4.70188","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T14:03:36Z","timestamp":1769609016000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Immunostimulatory and Immunodynamic Modeling Analysis to Determine a Plausible Starting Dose of\n                    <scp>mRNA<\/scp>\n                    \u20104359 for Use in First\u2010In\u2010Human Trials"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6605-9222","authenticated-orcid":false,"given":"Stephen A.","family":"Greene","sequence":"first","affiliation":[{"name":"Moderna, Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhav","family":"Channavazzala","sequence":"additional","affiliation":[{"name":"Vantage Research, Inc.  Lewes Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3726-0167","authenticated-orcid":false,"given":"Bhairav","family":"Paleja","sequence":"additional","affiliation":[{"name":"Vantage Research, Inc.  Lewes Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harshbir Singh","family":"Sandhu","sequence":"additional","affiliation":[{"name":"Vantage Research, Inc.  Lewes Delaware USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rukmini","family":"Kumar","sequence":"additional","affiliation":[{"name":"Vantage Research, Inc.  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