Ep188: Art Krieg on Innate Immune System Activators for Cancer

What It Covers

Art Krieg, founder of Zola Therapeutics and pioneer of CpG DNA immunotherapy, explains how his new oligonucleotide drug candidate simultaneously activates TLR7, TLR8, and TLR9 receptors to mimic a retroviral infection signal, potentially converting immune-suppressive tumor environments into active cancer-killing responses across multiple solid tumor types.

Key Questions Answered

• •Innate immune quorum sensing: Tumors recruit immune cells by mimicking damaged tissue, triggering wound-repair responses instead of antiviral attack. Zola's approach delivers synthetic lipid particles containing both viral DNA and RNA signals to override this misdirection, telling immune cells a retrovirus is present and activating CD8 T cells that evolved specifically to kill virus-infected cells — the same mechanism needed to eliminate tumors.
• •TLR9-only limitation: Krieg's prior company Checkmate achieved a 20–25% response rate in checkpoint-refractory melanoma using a TLR9 agonist alone. The ceiling existed because myeloid suppressor cells in tumors lack TLR9 receptors, making them unresponsive. Adding TLR7 and TLR8 agonists targets those previously unreachable suppressive cells, addressing the core mechanism of immune tolerance that blocked higher response rates in earlier trials.
• •Cytokine storm avoidance: Conventional immune activators trigger inflammatory cytokines alongside antiviral responses, risking dangerous cytokine storm. Zola's triple-receptor agonist, tested in mice and monkeys at doses 100 times the expected human dose, produced strong interferon responses without inflammatory cytokine elevation — a profile no prior agent has demonstrated, potentially enabling safer dose escalation in future human trials.
• •IV delivery exploits tumor biology: Tumors cause surrounding immune cells to upregulate lipid uptake receptors to sample the local tissue environment. Zola's lipid-encapsulated particles administered intravenously are preferentially absorbed by these primed immune cells near tumors, enabling systemic delivery without requiring direct intratumoral injection. Early dog trials show tumor regression via IV dosing, including regression of tumors distant from the injection site.
• •Canine oncology as development accelerator: Zola is running pet dog cancer trials funded by the nonprofit Canine Cancer Alliance at a fraction of human trial costs — hundreds of thousands versus the $5 million needed for IND-enabling studies. Four of seven enrolled dogs show tumor regression across lung cancer, melanoma, fibrosarcoma, and hemangiosarcoma. This model allows dosing regimen optimization and translational data generation before human trials begin.
• •Serendipity-driven discovery methodology: Krieg's 1995 Nature paper identifying CpG DNA as an immune stimulant originated from control oligonucleotides — sequences designed to do nothing — that unexpectedly drove B cell proliferation stronger than anything previously published. The key insight came from recognizing that unmethylated cytosine-guanine sequences in bacterial DNA differ from methylated human DNA, giving the immune system a molecular signature to distinguish self from pathogen.