Targeted apoptotic immune modulator for the treatment of metastatic EGFR-positive solid tumors

Aberrant activation and overexpression of the epidermal growth factor receptor (EGFR) occurs in various solid cancers and often correlates with poor outcome. The clinical benefit from EGFR-targeted therapies is usually short-lived, with resistance being driven by tumor heterogeneity and an immunosuppressive tumor microenvironment (TME). To address these limitations, we developed Targeted Apoptotic Immune Modulators (TAIM), a nonviral nanoparticle platform for the targeted delivery of polyinosine:polycytosine (polyIC), to simultaneously induce tumor cell death and activate antitumor immunity. The first TAIM compound, TAR001, was designed as a systemic treatment against metastatic EGFR-positive solid cancers. Here, we present TAR001's multifaceted mode of action. We demonstrate that TAR001 is selective toward EGFR-overexpressing cancers, provoking a pattern recognition response, apoptosis, cytokine secretion, and antitumor immunity. TAR001 modulates the TME, recruiting and activating both innate and adaptive immune cells. Systemic delivery of TAR001 markedly extends survival and inhibits tumor growth in multiple murine tumor models. TAR001 represents an innovative, safe, multimodal treatment approach with the potential to benefit patients with metastatic head and neck, non-small cell lung cancer, colorectal, renal, and triple-negative breast cancers. This unique modality utilizes a broad range of mechanisms to overcome the tumor's ability to escape apoptosis and immune cell activation.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-05-29
DOI
https://doi.org/10.1073/pnas.2500489122
Citations
1
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
1.05
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article

Targeted apoptotic immune modulator for the treatment of metastatic EGFR-positive solid tumors

Lucia D’Amico, Michal Skowicki, Maurizio Scaltriti, Derrick Broka et al.
1 citations
Proceedings of the National Academy of Sciences
Cancer Immunotherapy and Biomarkers
1.05
article

Targeted apoptotic immune modulator for the treatment of metastatic EGFR-positive solid tumors

Lucia D’Amico, Michal Skowicki, Maurizio Scaltriti, Derrick Broka, Elisa de Stanchina, Esteban Pombo‐Villar, Alexei Shir, Athanasia Dasargyri, Doriano Fabbro, Joerg Schreiber, Cornelia G. Palivan, Meera Saxena, Maya Zigler, Babette Schade, Laura Baldino, M. Okoniewski, Eric Kitas, Aviram Mizrachi, Elad Hikri, Alfred Zippelius, Besnik Qeriqi, Yaakov Benenson, Caroline De Feyter, David Colecchia, A Levitzki, Davor Bajic, Anita Jarzębińska, Mélanie Buchi, Shoshana Klein
article en
1 citations

Abstract

Aberrant activation and overexpression of the epidermal growth factor receptor (EGFR) occurs in various solid cancers and often correlates with poor outcome. The clinical benefit from EGFR-targeted therapies is usually short-lived, with resistance being driven by tumor heterogeneity and an immunosuppressive tumor microenvironment (TME). To address these limitations, we developed Targeted Apoptotic Immune Modulators (TAIM), a nonviral nanoparticle platform for the targeted delivery of polyinosine:polycytosine (polyIC), to simultaneously induce tumor cell death and activate antitumor immunity. The first TAIM compound, TAR001, was designed as a systemic treatment against metastatic EGFR-positive solid cancers. Here, we present TAR001's multifaceted mode of action. We demonstrate that TAR001 is selective toward EGFR-overexpressing cancers, provoking a pattern recognition response, apoptosis, cytokine secretion, and antitumor immunity. TAR001 modulates the TME, recruiting and activating both innate and adaptive immune cells. Systemic delivery of TAR001 markedly extends survival and inhibits tumor growth in multiple murine tumor models. TAR001 represents an innovative, safe, multimodal treatment approach with the potential to benefit patients with metastatic head and neck, non-small cell lung cancer, colorectal, renal, and triple-negative breast cancers. This unique modality utilizes a broad range of mechanisms to overcome the tumor's ability to escape apoptosis and immune cell activation.

Proceedings of the National Academy of SciencesVol. 122(22)
Memorial Sloan Kettering Cancer Center (US), Tel Aviv University (IL), University of Basel (CH), Hebrew University of Jerusalem (IL), Rabin Medical Center (IL), University Hospital of Basel (CH), ETH Zurich (CH), DecImmune Therapeutics (United States) (US), NBE Therapeutics (Switzerland) (CH), Department of Biomedicine Basel (CH), École Polytechnique Fédérale de Lausanne (CH)
Good health and well-being
Openalex Percentile: Top 21%
Cancer Immunotherapy and Biomarkers
1.05
DOIOpen Access PDFOpenAlex
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