Local T-cell engager secretion reprograms endogenous antitumor immunity and enhances CAR-T cell persistence in solid tumors
11 affiliations
- 1Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain
- 2Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
- 3CNIO-HMRIB Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- 4Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
- 5Protein Production Unit, Structural Biology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- 6Alamo Blanco Research Association, Granada, Spain
- 7Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
- 8Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, and School of Immunology and Microbial Sciences, Kings College London, London, UK
- 9Joan Reece Chair of Immuno-oncology, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, and School of Immunology and Microbial Sciences, Kings College London, London, UK
- 10Cancer Immunotherapy Research Group, Hospital del Mar Research Institute Barcelona (HMRIB), Barcelona, Spain
- 11Banc de Sang i Teixits (BST), Barcelona, Spain
Abstract
Background: Adoptive T-cell therapies can mediate potent antitumor activity, yet their efficacy against solid tumors remains limited by antigen heterogeneity, tumor escape, and insufficient induction of endogenous antitumor immunity. Whether distinct T cell-redirecting strategies differentially engage host immune responses that contribute to durable tumor control remains poorly understood.
Methods: Here, we compared conventional chimeric antigen receptor (CAR)-T cells, systemic T-cell engagers (TCEs), TCE-secreting (STAb)-T cells, and dual-targeting CAR–STAb-T cells in immunocompetent mouse models of high-grade glioma. CAR–STAb-T cells combined an EGFRvIII-specific CAR with local secretion of a B7-H3-targeted TCE, enabling simultaneous direct tumor targeting and recruitment of endogenous bystander T cells. Using heterogeneous tumor models, together with functional immune profiling and T-cell receptor repertoire sequencing, we investigated the mechanisms underlying durable antitumor responses.
Results: Local TCE secretion markedly enhanced tumor control compared with either CAR-T cells or systemic TCE administration alone. STAb-T and CAR–STAb-T therapies prevented antigen-loss escape, expanded endogenous tumor-reactive T-cell clonotypes, promoted epitope spreading, and generated durable memory responses capable of transferring protection to secondary tumor-bearing hosts. Notably, CAR–STAb-T cells uniquely combined robust endogenous immune priming with prolonged persistence of engineered T cells, resulting in superior tumor control. TCR repertoire analyses revealed preferential expansion of tumor-reactive clonotypes associated with specific antitumoral responses, linking therapeutic efficacy to diversification of host immunity.
Conclusions: These findings identify local engager secretion as a mechanism that converts engineered T cells from direct cytotoxic effectors into drivers of endogenous antitumor immunity. By coupling CAR-mediated persistence with TCE-driven recruitment of polyclonal host T cells, CAR–STAb-T cells overcome antigenic heterogeneity and establish durable immune surveillance, providing a framework for next-generation adoptive cell therapies in solid tumors.
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BibTeX
@article{arroyorodenas2026local,
title = {{Local T-cell engager secretion reprograms endogenous antitumor immunity and enhances CAR-T cell persistence in solid tumors}},
author = {Javier Arroyo-Ródenas and Alex Chen and Jason Tonne and Jill Thompson and Thanich Sangsuwannukul and María Rivas-Sánchez and David Sánchez-Alonso and Raquel Tobes and Yin M Chen and Eduardo Pareja and Jorge Martínez-Torrecuadrada and Anaïs Jiménez-Reinoso and Michael J Shapiro and Nicolas Sarbia and Shane Foo and Virginia Smith Shapiro and Richard Vile and Luis Alvarez-Vallina},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-016460},
url = {https://doi.org/10.1136/jitc-2026-016460},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Local T-cell engager secretion reprograms endogenous antitumor immunity and enhances CAR-T cell persistence in solid tumors
AU - Javier Arroyo-Ródenas
AU - Alex Chen
AU - Jason Tonne
AU - Jill Thompson
AU - Thanich Sangsuwannukul
AU - María Rivas-Sánchez
AU - David Sánchez-Alonso
AU - Raquel Tobes
AU - Yin M Chen
AU - Eduardo Pareja
AU - Jorge Martínez-Torrecuadrada
AU - Anaïs Jiménez-Reinoso
AU - Michael J Shapiro
AU - Nicolas Sarbia
AU - Shane Foo
AU - Virginia Smith Shapiro
AU - Richard Vile
AU - Luis Alvarez-Vallina
PY - 2026
DA - 2026/10/23
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-016460
UR - https://doi.org/10.1136/jitc-2026-016460
AB - Background: Adoptive T-cell therapies can mediate potent antitumor activity, yet their efficacy against solid tumors remains limited by antigen heterogeneity, tumor escape, and insufficient induction of endogenous antitumor immunity. Whether distinct T cell-redirecting strategies differentially engage host immune responses that contribute to durable tumor control remains poorly understood. Methods: Here, we compared conventional chimeric antigen receptor (CAR)-T cells, systemic T-cell engagers (TCEs), TCE-secreting (STAb)-T cells, and dual-targeting CAR–STAb-T cells in immunocompetent mouse models of high-grade glioma. CAR–STAb-T cells combined an EGFRvIII-specific CAR with local secretion of a B7-H3-targeted TCE, enabling simultaneous direct tumor targeting and recruitment of endogenous bystander T cells. Using heterogeneous tumor models, together with functional immune profiling and T-cell receptor repertoire sequencing, we investigated the mechanisms underlying durable antitumor responses. Results: Local TCE secretion markedly enhanced tumor control compared with either CAR-T cells or systemic TCE administration alone. STAb-T and CAR–STAb-T therapies prevented antigen-loss escape, expanded endogenous tumor-reactive T-cell clonotypes, promoted epitope spreading, and generated durable memory responses capable of transferring protection to secondary tumor-bearing hosts. Notably, CAR–STAb-T cells uniquely combined robust endogenous immune priming with prolonged persistence of engineered T cells, resulting in superior tumor control. TCR repertoire analyses revealed preferential expansion of tumor-reactive clonotypes associated with specific antitumoral responses, linking therapeutic efficacy to diversification of host immunity. Conclusions: These findings identify local engager secretion as a mechanism that converts engineered T cells from direct cytotoxic effectors into drivers of endogenous antitumor immunity. By coupling CAR-mediated persistence with TCE-driven recruitment of polyclonal host T cells, CAR–STAb-T cells overcome antigenic heterogeneity and establish durable immune surveillance, providing a framework for next-generation adoptive cell therapies in solid tumors.
SN - 2051-1426
ER -