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Published on: August 11, 2017
Targeted apoptotic immune modulator for the treatment of metastatic EGFR-positive solid tumors
Derrick Broka1, Shoshana Klein2, Alexei Shir1,2
1TargImmune Therapeutics, Basel 4057, Switzerland.
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.
Insights
Targeted Apoptotic Immune Modulators (TAIM) offer a novel approach to combat EGFR-overexpressing cancers by inducing tumor cell death and activating immune responses. This nanoparticle platform, TAR001, shows promise in extending survival and inhibiting tumor growth in preclinical models.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Aberrant epidermal growth factor receptor (EGFR) signaling drives various solid cancers, often leading to poor prognoses.
- EGFR-targeted therapies face limitations due to tumor resistance, heterogeneity, and an immunosuppressive tumor microenvironment (TME).
Purpose of the Study:
- To investigate the multifaceted mode of action of TAR001, a novel Targeted Apoptotic Immune Modulator (TAIM) nanoparticle.
- To evaluate TAR001's efficacy in inducing tumor cell death and activating antitumor immunity against EGFR-overexpressing cancers.
Main Methods:
- Development of a nonviral nanoparticle platform (TAIM) for targeted delivery of polyinosine:polycytosine (polyIC).
- Assessment of TAR001's selectivity, immune response induction, and TME modulation in EGFR-overexpressing cancer models.
- Evaluation of systemic delivery efficacy in murine tumor models.
Main Results:
- TAR001 demonstrates selectivity for EGFR-overexpressing cancers, inducing apoptosis, cytokine secretion, and antitumor immunity.
- TAR001 effectively modulates the TME, recruiting and activating innate and adaptive immune cells.
- Systemic TAR001 delivery significantly extends survival and inhibits tumor growth across multiple preclinical models.
Conclusions:
- TAR001 represents an innovative, safe, and multimodal treatment strategy for metastatic EGFR-positive solid cancers.
- This approach overcomes tumor resistance mechanisms by simultaneously inducing apoptosis and immune activation.
- TAR001 holds potential for treating metastatic head and neck, non-small cell lung, colorectal, renal, and triple-negative breast cancers.
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