Targeted apoptotic immune modulator for the treatment of metastatic EGFR-positive solid tumors Journal Article
| Authors: | Broka, D.; Klein, S.; Shir, A.; Schade, B.; Saxena, M.; Dasargyri, A.; Jarzebinska, A.; De Feyter, C.; Bajic, D.; Colecchia, D.; D'Amico, L.; Kitas, E.; Hikri, E.; Skowicki, M. J.; Okoniewski, M. J.; Baldino, L.; Qeriqi, B.; de Stanchina, E.; Schreiber, J.; Buchi, M.; Palivan, C. G.; Benenson, Y.; Zippelius, A.; Fabbro, D.; Scaltriti, M.; Mizrachi, A.; Levitzki, A.; Pombo-Villar, E.; Zigler, M. |
| Article Title: | Targeted apoptotic immune modulator for the treatment of metastatic EGFR-positive solid tumors |
| 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. Copyright © 2025 the Author(s). |
| Keywords: | controlled study; unclassified drug; human cell; genetics; microscopy; nonhuman; solid tumor; flow cytometry; antineoplastic agent; neoplasm; neoplasms; colorectal cancer; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; stat1 protein; metastasis; apoptosis; epidermal growth factor receptor; interleukin 13; interleukin 4; animal experiment; animal model; immunoglobulin enhancer binding protein; caspase 3; antineoplastic activity; cytotoxicity; drug effect; pathology; cell line, tumor; cetuximab; enzyme linked immunosorbent assay; lung metastasis; immunology; chemistry; immunotherapy; gamma interferon; tumor cell line; western blotting; neoplasm metastasis; tumor immunity; nanoparticles; nanoparticle; egfr; tumor growth; kidney cancer; drug therapy; gamma interferon inducible protein 10; cytokine release; immunosuppressive treatment; cell activation; beta interferon; immunocompetent cell; monocyte chemotactic protein 1; drug delivery system; egfr protein, human; lysosome associated membrane protein 1; tumor necrosis factor; targeted cancer therapy; programmed death 1 ligand 1; non small cell lung cancer; tumor microenvironment; high mobility group b1 protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; triple negative breast cancer; peptides and proteins; rantes; interferon regulatory factor 3; erbb receptors; vinculin; humans; human; female; article; cancer cell line; confocal laser scanning microscopy; mcf-7 cell line; wi-38 cell line; polyinosinic acid; mda-mb-468 cell line; b16-f10 cell line; chemicals and drugs; metastatic head and neck cancer; bt-20 cell line; polyic; isg15 protein; polycytosine; tar001; targeted apoptotic immune modulators; a-431 cell line; hcc-70 cell line; live cell microscopy; metastatic egfr-positive solid tumor; renca-hegfr cell line; u-138mg cell line |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 122 |
| Issue: | 22 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2025-01-01 |
| Start Page: | e2500489122 |
| Language: | English |
| DOI: | 10.1073/pnas.2500489122 |
| PUBMED: | 40440060 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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