CD4+ tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts

Sep 21, 2026

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Adoptive transfer of tumor-infiltrating lymphocytes (TIL) shows strong results in melanoma, but benefits in other cancers remain limited, even when TIL are engineered to enhance tumor homing, cytotoxicity, or resistance to exhaustion. Ex vivo expansion can shift T cell clonal composition and may reduce tumor reactivity, threatening TIL therapy success. Here, TIL secreting anti-EGFR × anti-CD3 T cell-engagers (TILSTAb) were studied in NSCLC TCRβ repertoire and in vitro/in vivo PDX models. The standard expansion protocol erased tumor-dominant clones and increased virus-reactive clonotypes. TILSTAb achieved antitumor activity intratumorally or systemically, with regression driven by CD4+ TIL bearing non-tumor-dominant clonotypes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Results and findings

Materials and methods (TILSTAb generation and PDX models)

Article history and keywords

ONCOIMMUNOLOGY 2024, VOL. 13, NO. 1, 2392897 [https://doi.org/10.1080/2162402X.2024.2392897](https://doi.org/10.1080/2162402X.2024.2392897) BRIEF REPORT CD4+ tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts Anaïs Jiménez-Reinoso a,b,c, Magdalena Molero-Abraham d,e, Cristina Cirauqui e, Belén Blanco a,b,c, Eva M. Garrido-Martin e,f, Daniel Nehme-Álvarez a,b, Carmen Domínguez-Alonso a,b,c, Ángel RamírezFernández a,b,c, Laura Díez-Alonso a,b,c, Ángel Nuñez-Buiza e, África González-Murillo g,h,i, Raquel Tobes j, Eduardo Pareja j, Manuel Ramírez-Orellana g,h,i, José Luis Rodriguez-Peralto f,k,l,m, Irene Ferrer e,f, Jon Zugazagoitia d,e,f,n, Luis Paz-Ares e,f,n,o, and Luis Álvarez-Vallina a,b,c* aCancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain; bImmuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain; cH12O-CNIO Cancer Immunotherapy Clinical Research Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; dTumor Microenvironment and Immunotherapy Research Group, Madrid, Spain; eH12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Sanitaria 12 de Octubre (imas12), CNIO, Madrid, Spain; fSpanish Center for Biomedical Research Network in Oncology (CIBERONC), Madrid, Spain; gAdvanced Therapies Unit, Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; hFundación de Investigación Biomédica, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; iInstituto de Investigación Sanitaria La Princesa, Madrid, Spain; jAlamo blanco Research Association, Granada, Spain; kDepartment of Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain; lDepartment of Pathology, Complutense University, Madrid, Spain; mCutaneous Oncology Group, Madrid, Spain; n Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain; o Department of Medicine, Complutense University, Madrid, Spain ABSTRACT Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production ofbispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRβ repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TILSTAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TILSTAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR+ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4+ TIL bearing non-tumor dominant clonotypes. ARTICLE HISTORY Received 23 June 2024 Revised 11 August 2024 Accepted 12 August 2024 KEYWORDS Adoptive cell therapy; bispecific T cell-engagers; cytotoxic CD4+ TIL; solid tumors; tumor-infiltrating lymphocytes Introduc

FAQs

Why do TIL therapies often show limited benefits outside melanoma?

Limited benefits are associated with modest outcomes in non-melanoma tumors, where ex vivo TIL expansion can change T cell clonal composition and potentially compromise tumor reactivity.

What change in the T cell repertoire was observed after the standard TIL expansion protocol?

The protocol promotes loss of tumor-dominant T cell clones and allows overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors.

How do TILSTAb mediate tumor regression in the described NSCLC models?

Tumor regression is mediated by TCE-redirected CD4+ TIL carrying non-tumor-dominant clonotypes, demonstrated both in vitro and in vivo in patient-derived xenograft models.

Sep 21, 2026

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