Ep188: Art Krieg on Innate Immune System Activators for Cancer

Episode Summary

Executive Summary: Art Krieg traces his path from rheumatology and academic immunology to serial biotech entrepreneurship, centered on oligonucleotide immune activators. He explains how CPG DNA led to vaccine and cancer programs, why TLR9 alone was insufficient, and why Zola now combines TLR7/8/9 activation in a synthetic viral mimic to trigger potent anti-tumor CD8 T-cell responses with low toxicity.

Main Topics: Krieg’s path into immunology and medicine (Priority: 5/5): He recounts a childhood shaped by moves across the U.S., early love of science, and a formative lupus case that showed him the immune system’s power and drove him toward rheumatology and immunology. Origins of oligonucleotide therapeutics (Priority: 5/5): Krieg describes his early fascination with antisense oligos as rational, sequence-specific drugs that could reach undruggable intracellular targets, even before delivery was well understood. Discovery of CpG DNA and birth of innate immune stimulation (Priority: 5/5): At Iowa, he found that certain control DNA oligos unexpectedly stimulated B cells; this led to the CpG motif discovery and the realization that unmethylated CpG DNA is sensed as foreign, eventually linked to TLR9. Commercializing CpG through Coley and Checkmate (Priority: 5/5): He moved discoveries into companies, with mixed results: vaccine adjuvants and some immune programs succeeded, while hepatitis C, allergy, and pivotal cancer trials had setbacks; later, a stronger double-stranded CpG construct at Checkmate produced meaningful melanoma responses and acquisition by Regeneron. Why TLR9 was not enough and the Zola hypothesis (Priority: 5/5): Krieg argues that tumors suppress immunity through multiple cell types that TLR9 alone doesn’t activate. Zola is designed to mimic retroviral particles and engage TLR7, TLR8, and TLR9 together to better induce antiviral-like, anti-tumor immunity. Safety, dosing, and early preclinical/veterinary signals (Priority: 4/5): He reports that the new Zola compounds triggered anti-tumor activity in mice, were tolerated in monkeys at high exposures without cytokine storm, and are showing early regression signals in pet dogs with cancers. Industry context and future positioning (Priority: 4/5): Krieg contrasts current VC caution in immunotherapy with continued pharma interest in immune-engaging modalities, arguing Zola could become a low-cost, broadly applicable platform complementary to checkpoint inhibitors and bispecifics.

Key Arguments: A formative lupus case demonstrated how powerfully the immune system can destroy tissue, motivating a career in immunology and rheumatology. Antisense oligonucleotides were compelling because they offered rational, sequence-specific targeting of intracellular biology that antibodies could not reach. The CpG motif mattered because unmethylated bacterial/viral DNA is recognized as foreign; methylation abolished the stimulatory effect, proving a distinct innate immune sensing mechanism. Cancer immunotherapy succeeded only when it learned to both release immune brakes and press the gas; checkpoint inhibitors alone are insufficient in many solid tumors. TLR9 agonism produced real responses, but only in a subset of tumor immune cells; suppressive tumor myeloid cells lacked TLR9 and remained a barrier. The next advance is to mimic a retroviral infection more completely by activating TLR7/8/9 together, thereby mobilizing the broader innate immune network needed for durable CD8 T-cell responses. Zola’s particle-based delivery may be safer than expected because it induced interferon responses without the cytokine storm typically feared with strong immune activators. A universal, low-cost immune activator could complement or precede personalized vaccines, CAR-T, and checkpoint therapy, especially for hard-to-treat solid tumors and liver metastases.

Data Points: Age at move to Alaska: 3 - Family relocated from Cleveland to Fairbanks/Anchorage when Krieg was three. Years of medical school: 1979-1983 - He attended medical school during the late 1970s and early 1980s. Years to publish CpG discovery: ~2 years - He spent about two years from initial observation to understanding the CpG mechanism. CpG Nature publication year: 1995 - He published the CpG discovery in Nature in 1995. Company named after: William B. Coley - Coley Pharmaceutical Group was named after the father of cancer immunotherapy. Cancer immunotherapy trial size at Checkmate: 40 patients - Advanced melanoma patients treated with the Checkmate CpG DNA monotherapy program. RECIST responses: 8 of 40 - Responses observed in advanced melanoma patients treated with monotherapy. Non-RECIST responses: 1 patient - An additional patient had a response not captured by RECIST. Response rate: 20-22% - Approximate monotherapy response rate in heavily pretreated melanoma patients. Duration of response (monotherapy): <6 months - Responses with monotherapy were shorter than six months. Duration of response (combination): >2 years - Responses lasted over two years when combined with a checkpoint inhibitor. Monkey safety margin: 100x human dose - No apparent toxicity was seen in monkeys at exposures up to 100 times expected human dose. Dogs treated: 7 - Early veterinary testing in pet dogs with tumors. Dogs showing clear regression: 4 - Four of seven dogs appeared to have clear tumor regression. Pfizer acquisition of Coley: 2008 - Coley was acquired by Pfizer in 2008. Regeneron acquisition of Checkmate: $250 million - Checkmate Pharmaceuticals was acquired by Regeneron in 2022.

Pivotal Quotes: "you've already made the decision. You just don't know it yet." — Joe Davies (quoted by Art Krieg): Advice that convinced Krieg to leave academia and move into industry to pursue his discovery. "This is the one big discovery that I would probably ever make in my scientific career, and I really felt I wanted to follow this through." — Art Krieg: Explaining why he left a tenured academic path to build companies around CpG DNA. "we have to tell those immune cells that this tissue is infected by a virus if we want to induce the antiviral response that leads to CD8 T cells." — Art Krieg: Core Zola hypothesis: mimic viral infection to drive anti-tumor immunity.

Implications: If Zola’s platform works, it could become a broadly usable, low-cost immune-activation backbone for cancer therapy and vaccines, especially where checkpoint blockade is weak. It may also reshape the field’s focus back toward innate immune activation rather than only additional checkpoints.