{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T05:36:53Z","timestamp":1776836213957,"version":"3.51.2"},"posted":{"date-parts":[[2024,7,5]]},"group-title":"Oncology","reference-count":52,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Although immune check-point inhibitors (CPIs) revolutionized treatment of Merkel cell carcinoma (MCC), patients with CPI-refractory MCC lack effective therapy. More than 80% of MCC express T-antigens encoded by Merkel cell polyomavirus, which is an ideal target for T-cell receptor (TCR)-based immunotherapy. However, MCC often repress HLA expression, requiring additional strategies to reverse the downregulation for allowing T cells to recognize their targets. We identified TCR\n                  <jats:sub>MCC1<\/jats:sub>\n                  that recognizes a T-antigen epitope restricted to human leukocyte antigen (HLA)-A*02:01. Seven CPI-refractory metastatic MCC patients received CD4 and CD8 T cells transduced with TCR\n                  <jats:sub>MCC1<\/jats:sub>\n                  (T\n                  <jats:sub>TCR-MCC1<\/jats:sub>\n                  ) preceded either by lymphodepleting chemotherapy or an HLA-upregulating regimen (single-fraction radiation therapy (SFRT) or systemic interferon gamma (IFN\u03b3)) with concurrent avelumab. Two patients who received preceding SFRT and IFN\u03b3 respectively experienced tumor regression. One experienced regression of 13\/14 subcutaneous lesions with 1 \u2018escape\u2019 lesion and the other had delayed tumor regression in all lesions after initial progression. Although T\n                  <jats:sub>TCR-MCC1<\/jats:sub>\n                  cells with an activated phenotype infiltrated tumors including the \u2018escape\u2019 lesion, all progressing lesions transcriptionally lacked HLA expression. While SFRT\/IFN\u03b3 did not immediately upregulate tumor HLA expression, a secondary endogenous antigen-specific T cell infiltrate was detected in one of the regressing tumors and associated with HLA upregulation, indicating in situ immune responses have the potential to reverse HLA downregulation. Indeed, supplying a strong co-stimulatory signal via a CD200R-CD28 switch receptor allows T\n                  <jats:sub>TCR-MCC1<\/jats:sub>\n                  cells to control HLA-downregulated MCC cells in a xenograft mouse model, upregulating HLA expression. Our results demonstrate the potential of TCR gene therapy for metastatic MCC and propose a next strategy for overcoming epigenetic downregulation of HLA in MCC.\n                <\/jats:p>","DOI":"10.1101\/2024.07.01.24309780","type":"posted-content","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T12:10:27Z","timestamp":1720181427000},"source":"Crossref","is-referenced-by-count":2,"title":["Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory Merkel Cell Carcinoma"],"prefix":"10.64898","author":[{"given":"Yuta","family":"Asano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Veatch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"McAfee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob","family":"Bakhtiari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shihong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Mazziotta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly 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