{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T18:10:44Z","timestamp":1788977444871,"version":"build-2803163510"},"reference-count":73,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"866","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01CA225517"],"award-info":[{"award-number":["P01CA225517"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014547","name":"Parker Institute for Cancer Immunotherapy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014547","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016508","name":"bluebird bio","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016508","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Affini-T Therapeutics, Inc."},{"name":"Fund for Science and Technology"},{"name":"Besoz Immunotherapy Fund"},{"name":"Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Center"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,9,9]]},"abstract":"<jats:p>\n                    Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR)\n                    <jats:sub>MCC1<\/jats:sub>\n                    , a highly avid, HLA-A*02:01\u2013restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen\n                    <jats:sub>15\u201323<\/jats:sub>\n                    . Seven patients with ICI-refractory metastatic MCPyV\n                    <jats:sup>+<\/jats:sup>\n                    MCC received TCR\n                    <jats:sub>MCC1<\/jats:sub>\n                    -transduced cells (T\n                    <jats:sub>TCR-MCC1<\/jats:sub>\n                    cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). T\n                    <jats:sub>TCR-MCC1<\/jats:sub>\n                    cells trafficked to tumor sites and expressed a gene expression profile compatible with T cell activation, with tumor regression observed in two patients. However, therapeutic activity was limited by HLA class I silencing, a common mechanism of immune escape in MCC. In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying that robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 T\n                    <jats:sub>TCR-MCC1<\/jats:sub>\n                    cells to coexpress CD8\u03b1\u03b2 and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell costimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLA\n                    <jats:sup>low<\/jats:sup>\n                    MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV\n                    <jats:sup>+<\/jats:sup>\n                    MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aea8773","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:58:12Z","timestamp":1788976692000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4720-2238","authenticated-orcid":true,"given":"Yuta","family":"Asano","sequence":"first","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6543-9255","authenticated-orcid":true,"given":"Joshua R.","family":"Veatch","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA."},{"name":"Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7858-8308","authenticated-orcid":true,"given":"Cheng-Jung","family":"Sung","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2596-1872","authenticated-orcid":true,"given":"Tzu-Hao","family":"Tang","sequence":"additional","affiliation":[{"name":"Translational Science and 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