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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (29)
Derrick Broka
TargImmune Therapeutics
Shoshana Klein
Department of Biological Chemistry, Silberman Life Sciences Institute, The Hebrew University of Jerusalem, Edmond J. Safra Campus
Alexei Shir
TargImmune Therapeutics
Babette Schade
TargImmune Therapeutics
Meera Saxena
TargImmune Therapeutics
Athanasia Dasargyri
TargImmune Therapeutics
Anita Jarzebinska
TargImmune Therapeutics
Caroline De Feyter
TargImmune Therapeutics
Davor Bajic
TargImmune Therapeutics
David Colecchia
TargImmune Therapeutics
Lucia D'Amico
TargImmune Therapeutics
Eric Kitas
TargImmune Therapeutics
Elad Hikri
Department of Otorhinolaryngology, Head and Neck Surgery, Rabin Medical Center
Michal Jerzy Skowicki
Department of Chemistry, University of Basel
Michal Jerzy Okoniewski
Scientific IT Services ID, ETH
Laura Baldino
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Besnik Qeriqi
Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center
Elisa de Stanchina
Joerg Schreiber
Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology
Melanie Buchi
Department of Biomedicine, University of Basel and University Hospital
Cornelia G. Palivan
Department of Chemistry, University of Basel
Yaakov Benenson
Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology
Alfred Zippelius
Doriano Fabbro
TargImmune Therapeutics
Maurizio Scaltriti
Aviram Mizrachi
Department of Otorhinolaryngology, Head and Neck Surgery, Rabin Medical Center
Alexander Levitzki
Department of Biological Chemistry, Silberman Life Sciences Institute, The Hebrew University of Jerusalem, Edmond J. Safra Campus
Esteban Pombo-Villar
TargImmune Therapeutics
Maya Zigler
TargImmune Therapeutics