{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T12:14:48Z","timestamp":1779279288381,"version":"3.51.4"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Metastatic soft tissue sarcomas (STSs) are a heterogeneous group of rare mesenchymal tumors whose treatment options are limited. Our group has been interested in utilizing the synthetic toll-like receptor 4 (TLR4) agonist, glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE), in patients with advanced STSs. Here, we report a case series of three patients with metastatic leiomyosarcoma who had superficial lesions amenable to intratumoral (IT) injection. We explored the safety, tolerability, and immunologic effects of IT GLA-SE given at 20 \u03bcg weekly for 12 weeks, both alone and in combination with radiotherapy. In this small case series, treatment was well tolerated, with no serious adverse events observed. Clinically, although no patient had significant tumor shrinkage, two had notable stability in their target lesions despite systemic disease progression. Immunologically, IT GLA-SE induced a clonal expansion of T cells intratumorally in one patient and in peripheral blood in another, suggesting an antitumor effect both at the site of injection and systemically. Moreover, GLA-SE elicited clonal expansion of systemic T cells targeting a well-known immunogenic cancer antigen, NY-ESO-1. The augmented expression of T cells targeting NY-ESO-1 in the systemic circulation of our patient following IT-GLA-SE warrants further investigation, given the promising role of NY-ESO-1 in current and future T-cell based immunotherapies. Together, these findings demonstrate the potential of IT GLA-SE to elicit antigen-specific T cell clonal expansion as a component of immunotherapeutic strategies to combat metastatic STSs. Expanded studies are needed to explore the clinical and immunologic effects of IT GLA-SE, particularly in combination with other immunotherapies.<\/jats:p>","DOI":"10.3389\/fonc.2026.1829331","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T11:55:03Z","timestamp":1779278103000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Intratumoral TLR4 agonist therapy elicits antigen-specific T cell clonal expansion in metastatic leiomyosarcoma: a case series"],"prefix":"10.3389","volume":"16","author":[{"given":"Jessica S.","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medicine, Northwestern University Feinberg School of Medicine","place":["Chicago, IL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana C. 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