Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma

Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR) MCC1 , a highly avid, HLA-A*02:01–restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen 15–23 . Seven patients with ICI-refractory metastatic MCPyV + MCC received TCR MCC1 -transduced cells (T TCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). T TCR-MCC1 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 TCR-MCC1 cells to coexpress CD8αβ 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 low MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV + MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.

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Publication Details

Journal
Science Translational Medicine
Published
2026-09-09
DOI
https://doi.org/10.1126/scitranslmed.aea8773
Primary Topic
Polyomavirus and related diseases
Type
article
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article

Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma

Colton W Smith, Tianzi Zhang, Raphaël Gottardo, Yuta Asano et al.
Science Translational Medicine
Polyomavirus and related diseases
article

Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma

Colton W Smith, Tianzi Zhang, Raphaël Gottardo, Yuta Asano, David M. Koelle, Francesco Mazziotta, Shannon K. Oda, Kelly G. Paulson, Philip D. Greenberg, Valentin Voillet, Heather Herd Gustafson, Shailender Bhatia, Aude G. Chapuis, Anna Elz, Cheng-Jung Sung, Thomas M. Schmitt, Evan Hall, Lauren Martin, Evan W. Newell, Cecilia C.S. Yeung, Yapeng Su, Seiji Natsuki, Paul Nghiem, Joshua Veatch, Daniel Chen, Tzu-Hao Tang, Jakob Bakhtiari, T Gooley, Alessandro M. Rizzi, Jianhong Cao, Megan McAfee, Daniel Hunter, Bo Lee, Brandon Seaton
article en

Abstract

Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR) MCC1 , a highly avid, HLA-A*02:01–restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen 15–23 . Seven patients with ICI-refractory metastatic MCPyV + MCC received TCR MCC1 -transduced cells (T TCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). T TCR-MCC1 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 TCR-MCC1 cells to coexpress CD8αβ 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 low MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV + MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.

Science Translational MedicineVol. 18(866)
University of Washington (US), Centre Hospitalier Universitaire Vaudois (CH), Fred Hutch Cancer Center (US), Parker Institute for Cancer Immunotherapy (US), Center for Cancer and Blood Disorders (US), Benaroya Research Institute, École Polytechnique Fédérale de Lausanne (CH), University of Lausanne (CH)
Good health and well-being
Openalex Percentile: Top 13%
Polyomavirus and related diseases
DOISourceOpenAlex
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