Enlisting the Innate Immune System to Fight Cancer and other Diseases

Episode Summary

Executive Summary: The episode features an interview with Silverback Therapeutics CEO Peter Thompson on the company’s ImmunoTAC platform, which aims to systemically deliver antibody conjugates that locally activate the innate immune system in HER2-expressing tumors. Thompson explains why the company targets TLR8 on myeloid cells, how the approach may avoid systemic cytokine toxicity, and why it could complement checkpoint inhibitors. He also outlines a broader pipeline in fibrosis and infectious disease and says the first clinical trial is expected next year.

Main Topics: Adaptive vs. innate immunity (Priority: 5/5): Thompson contrasts T-cell/B-cell-driven adaptive immunity with the innate immune system’s myeloid-cell-mediated recognition of pathogens and danger signals. ImmunoTAC platform design (Priority: 5/5): Silverback’s platform is designed to enable systemic dosing while producing localized immune activation in diseased tissue, reducing the toxicity seen with broadly acting innate agonists. SBT-6050 lead program and HER2 targeting (Priority: 5/5): The lead candidate homes to HER2-expressing tumors and activates myeloid cells locally through TLR8, aiming to trigger anti-tumor immunity in HER2-positive cancers. Why TLR8 was selected (Priority: 4/5): Thompson argues TLR8 is best suited to the relevant myeloid populations in tumors and avoids broader receptor expression that could create safety issues; he also notes its human biology is understudied because rodents lack a functional homolog. Safety and localization of innate immune activation (Priority: 5/5): A central concern is cytokine release and systemic toxicity from innate immune stimulation; Silverback says AACR data showed strong anti-tumor activity without peripheral cytokine release or safety problems. Potential synergy with checkpoint inhibitors (Priority: 4/5): The platform may convert myeloid-rich, T-cell-poor tumors into a more permissive environment, potentially improving responses to PD-1/PD-L1 blockade and supporting combination use. Pipeline expansion and clinical path (Priority: 3/5): Beyond oncology, Silverback is exploring fibrosis and infectious disease applications, with first clinical development of SBT-6050 planned for the following year.

Key Arguments: The innate immune system can be therapeutically powerful, but only if activation is localized enough to avoid systemic toxicities. Silverback’s core innovation is a composition class that allows systemic administration while generating local activity in the tumor microenvironment. SBT-6050 targets HER2-expressing tumors and activates TLR8 on human myeloid cells, aiming for focused anti-tumor immune activation. TLR8 was chosen because it is expressed on monocytes, macrophages, and classic dendritic cells, which are key anti-tumor myeloid populations. Unlike many innate immune agonists, the company says its AACR-disclosed data showed no evidence of peripheral cytokine release or safety issues. The therapy may work both as a single agent and in combination with checkpoint inhibitors by increasing immune infiltration and neoantigen responses. The mechanism could be relatively robust against tumor heterogeneity because it engages both myeloid responses and broader neoantigen-driven adaptive immunity. The platform is intended to extend beyond cancer into other diseases where systemically delivered but locally active agents could be useful.

Data Points: Lead candidate: SBT-6050 - Silverback’s lead immunotherapy program targeting HER2-expressing tumors Target receptor: TLR8 - Selected innate immune receptor used to activate myeloid cells in tumors Biomarker target: HER2 high and intermediate expression - Tumors the lead candidate is designed to home to and treat Expected clinical start: next year - Planned initiation of clinical development for SBT-6050 Tumor indications mentioned: breast cancer, non-small cell lung cancer, colorectal cancer - Examples of epithelial malignancies that may express HER2 and be eligible for the approach Immune-cell populations highlighted: monocytes, macrophages, classic dendritic cells - Human myeloid cells that express TLR8 and are central to the platform’s mechanism

Pivotal Quotes: "the idea that led to the jumping off point for the company was trying to develop a composition class that would allow for systemic administration of product that would be locally active" — Peter Thompson: Explaining the rationale behind the ImmunoTAC platform "these compounds are able to generate exuberant antitumor activity without any evidence of peripheral cytokine release or safety issues" — Peter Thompson: Describing AACR-disclosed preclinical safety and efficacy findings "the greater the population of what we used to call TILs... generally the higher the likelihood of response" — Peter Thompson: Discussing why checkpoint inhibitors work better in T-cell-inflamed tumors

Implications: If successful clinically, Silverback’s approach could expand innate-immune oncology beyond toxic systemic agonists, create new combination strategies with checkpoint inhibitors, and open a broader platform for other inflammatory diseases.