A Standalone PD-1 Chimeric Switch Receptor T-Cell Platform Expands the Therapeutic Window of PD-L1 Targeting in Solid Tumors
- 1Regenerative Immunotherapy & CAR-T Translational Research Program, Department of Cancer Biology, Division of Hematology and Medical Oncology, Department of Inte
Abstract
Programmed death-ligand 1 (PD-L1) is a promising therapeutic target owing to its broad expression on tumor cells and immunosuppressive myeloid cells within the tumor microenvironment (TME), providing an opportunity to target both cellular compartments. However, physiological PD-L1 expression in normal tissues poses a substantial risk of on-target/off-tumor toxicity, limiting the therapeutic window and clinical translation of PD-L1-targeted cellular therapies. Here, we developed a standalone programmed death-1 (PD-1) chimeric switch receptor (CSR) T-cell platform designed to preserve the therapeutic advantages of PD-L1 targeting while improving tumor-normal discrimination. Iterative receptor engineering, with antitumor activity and normal-cell reactivity evaluated as parallel selection criteria, identified two lead PD-1 CSR T-cell candidates. Compared with our previously developed antibody-based PD-L1 CAR T cells, the lead candidates retained potent PD-L1-specific cytotoxicity against tumor cells while exhibiting markedly reduced cytotoxicity against primary human small airway epithelial cells, astrocytes, renal epithelial cells, hepatocytes, and cardiomyocytes. They also efficiently eliminated PD-L1-positive immunosuppressive myeloid cells and mediated dual-compartment targeting of tumor and myeloid cells in three-dimensional (3D) multicellular tumor organoids. In vivo, both candidates suppressed tumor growth and prolonged survival in orthotopic breast cancer and patient-derived glioblastoma models after systemic and intracranial administration, respectively. Collectively, these findings establish PD-1 CSR T cells as a standalone therapeutic platform that expands the therapeutic window of PD-L1-targeted cellular therapy by preserving dual-compartment targeting of tumor and immunosuppressive myeloid cells while reducing normal-cell reactivity, providing a foundation for further clinical translation across solid tumors.
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BibTeX
@misc{luo2026standalone,
title = {{A Standalone PD-1 Chimeric Switch Receptor T-Cell Platform Expands the Therapeutic Window of PD-L1 Targeting in Solid Tumors}},
author = {Y. Luo and S. Guo and Y. Qie and B. Zhao and M. J. Ulloa-Navas and M. Brooks and V. Jones and T. Hundal and J. C. Chavez and Y. Lou and L. P. Deleyrolle and V. Velcheti and J. W. Jakub and R. Dronca and M. A. Kharfan-Dabaja and A. Quinones-Hinojosa and H. Qin},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764663},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764663v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Standalone PD-1 Chimeric Switch Receptor T-Cell Platform Expands the Therapeutic Window of PD-L1 Targeting in Solid Tumors
AU - Y. Luo
AU - S. Guo
AU - Y. Qie
AU - B. Zhao
AU - M. J. Ulloa-Navas
AU - M. Brooks
AU - V. Jones
AU - T. Hundal
AU - J. C. Chavez
AU - Y. Lou
AU - L. P. Deleyrolle
AU - V. Velcheti
AU - J. W. Jakub
AU - R. Dronca
AU - M. A. Kharfan-Dabaja
AU - A. Quinones-Hinojosa
AU - H. Qin
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764663
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764663v1
AB - Programmed death-ligand 1 (PD-L1) is a promising therapeutic target owing to its broad expression on tumor cells and immunosuppressive myeloid cells within the tumor microenvironment (TME), providing an opportunity to target both cellular compartments. However, physiological PD-L1 expression in normal tissues poses a substantial risk of on-target/off-tumor toxicity, limiting the therapeutic window and clinical translation of PD-L1-targeted cellular therapies. Here, we developed a standalone programmed death-1 (PD-1) chimeric switch receptor (CSR) T-cell platform designed to preserve the therapeutic advantages of PD-L1 targeting while improving tumor-normal discrimination. Iterative receptor engineering, with antitumor activity and normal-cell reactivity evaluated as parallel selection criteria, identified two lead PD-1 CSR T-cell candidates. Compared with our previously developed antibody-based PD-L1 CAR T cells, the lead candidates retained potent PD-L1-specific cytotoxicity against tumor cells while exhibiting markedly reduced cytotoxicity against primary human small airway epithelial cells, astrocytes, renal epithelial cells, hepatocytes, and cardiomyocytes. They also efficiently eliminated PD-L1-positive immunosuppressive myeloid cells and mediated dual-compartment targeting of tumor and myeloid cells in three-dimensional (3D) multicellular tumor organoids. In vivo, both candidates suppressed tumor growth and prolonged survival in orthotopic breast cancer and patient-derived glioblastoma models after systemic and intracranial administration, respectively. Collectively, these findings establish PD-1 CSR T cells as a standalone therapeutic platform that expands the therapeutic window of PD-L1-targeted cellular therapy by preserving dual-compartment targeting of tumor and immunosuppressive myeloid cells while reducing normal-cell reactivity, providing a foundation for further clinical translation across solid tumors.
ER -