{
  "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.\n\nMethods: 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.\n\nResults: 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.\n\nConclusions: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain",
    "Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain",
    "CNIO-HMRIB Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain",
    "Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA",
    "Protein Production Unit, Structural Biology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain",
    "Alamo Blanco Research Association, Granada, Spain",
    "Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA",
    "Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, and School of Immunology and Microbial Sciences, Kings College London, London, UK",
    "Joan 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",
    "Cancer Immunotherapy Research Group, Hospital del Mar Research Institute Barcelona (HMRIB), Barcelona, Spain",
    "Banc de Sang i Teixits (BST), Barcelona, Spain"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Javier Arroyo-Ródenas",
      "orcid": "0000-0003-1099-2018"
    },
    {
      "affs": [
        3
      ],
      "name": "Alex Chen"
    },
    {
      "affs": [
        3
      ],
      "name": "Jason Tonne"
    },
    {
      "affs": [
        3
      ],
      "name": "Jill Thompson",
      "orcid": "0000-0001-5005-7257"
    },
    {
      "affs": [
        3
      ],
      "name": "Thanich Sangsuwannukul"
    },
    {
      "affs": [
        4
      ],
      "name": "María Rivas-Sánchez"
    },
    {
      "affs": [
        4
      ],
      "name": "David Sánchez-Alonso"
    },
    {
      "affs": [
        5
      ],
      "name": "Raquel Tobes"
    },
    {
      "affs": [
        6
      ],
      "name": "Yin M Chen"
    },
    {
      "affs": [
        5
      ],
      "name": "Eduardo Pareja"
    },
    {
      "affs": [
        4
      ],
      "name": "Jorge Martínez-Torrecuadrada"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Anaïs Jiménez-Reinoso"
    },
    {
      "affs": [
        6
      ],
      "name": "Michael J Shapiro"
    },
    {
      "affs": [
        7
      ],
      "name": "Nicolas Sarbia"
    },
    {
      "affs": [
        7
      ],
      "name": "Shane Foo"
    },
    {
      "affs": [
        6
      ],
      "name": "Virginia Smith Shapiro",
      "orcid": "0000-0001-9978-341X"
    },
    {
      "affs": [
        3,
        6,
        8
      ],
      "name": "Richard Vile"
    },
    {
      "affs": [
        2,
        9,
        10
      ],
      "name": "Luis Alvarez-Vallina",
      "orcid": "0000-0003-3053-6757"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bsf1svjcqpjwk.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-016460",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13711572/",
  "id": "bsf1svjcqpjwk",
  "issns": [
    "2051-1426"
  ],
  "landing_url": "https://doi.org/10.1136/jitc-2026-016460",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "1506"
    ],
    [
      "heading",
      "2436"
    ],
    [
      "heading",
      "Immune Cell Therapies and Immune Cell Engineering"
    ],
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7223356859",
  "pdf_url": "https://jitc.bmj.com/content/14/10/e016460.full.pdf",
  "pmcid": "PMC13711572",
  "pmid": "42919626",
  "published": "2026-10-23",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/bsf1svjcqpjwk.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:19Z",
      "native_id": "PMC13711572",
      "source": "pmc",
      "url": "https://doi.org/10.1136/jitc-2026-016460"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|CAR-T cell therapy research",
      "subfield": "oncology"
    }
  ],
  "title": "Local T-cell engager secretion reprograms endogenous antitumor immunity and enhances CAR-T cell persistence in solid tumors",
  "title_text": "Local T-cell engager secretion reprograms endogenous antitumor immunity and enhances CAR-T cell persistence in solid tumors",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:19Z",
  "url": "https://research.draconitic.com/paper/bsf1svjcqpjwk",
  "venue": "Journal for Immunotherapy of Cancer",
  "versions": []
}