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

Authors

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

Published in

Science translational medicine. Volume 18. Issue 866. Pages eaea8773. Sep 09, 2026. Epub Sep 09, 2026.

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.

PMID:
42715345
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.