Experimental Therapeutics

Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) in preclinical models enhances single-agent immune checkpoint blockade

Under the leadership of Robert Timmerman, M.D., the UTSW Department of Radiation Oncology has developed PULSAR, a paradigm-changing radiation approach that leverages cancer cells' inherent DNA repair deficiencies and radiation sensitivity, allowing for higher effective doses while sparing normal tissues through the adaptive fractionation approach. The ultrafractionation of radiation delivery allows for personalized adjustment of the radiation field and dose based on treatment response, offering three key advantages over traditional daily fractions. Split course treatments are less toxic, long intervals between pulses facilitate adaptive doses, and these extended intervals may foster adaptive immunity. Research demonstrates that both radiation and immunotherapy sequencing, as well as radiation therapy fraction spacing, significantly affect combination treatment responses. Better tumor control was achieved by giving anti-PD-L1 therapy during or after radiation, with fractions spaced 10 days apart (PULSAR) achieving superior tumor control compared to traditional daily fractions. The study showed that CD8+ depleting antibody abrogated tumor control in PULSAR combination treatment, and certain treatment schedules induced immunologic memory.

A telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer

Jerry Shay, Ph.D., and colleagues have demonstrated that treatment with the nucleoside analog 6-thio-2'-deoxyguanosine (6-thio-dG) leads to telomere replication stress, resulting in increased micronuclei formation, generation of cytosolic double-stranded DNA, and cGAS-STING pathway activation. Since telomerase is active in ~85% of cancers but largely absent in normal somatic cells, this approach provides a cancer-selective therapeutic window. This process converts "immunologically cold" tumors to become sensitive to immune checkpoint inhibition by increasing both innate and adaptive immunity. In small cell lung cancer models, 6-thio-dG treatment specifically depletes cancer initiating cells (CICs) identified by their expression of L1CAM/CD133 and highest telomerase activity, while simultaneously activating type-I interferon signaling that leads to tumor immune visibility through STING pathway activation. The therapy also enhances sensitivity to radiation treatment in both syngeneic and humanized xenograft models. In hepatocellular carcinoma studies, telomere stress induced by 6-thio-dG increases both innate sensing and adaptive antitumor immunity, with extracellular high-mobility group box 1 protein acting as a damage-associated molecular pattern to elicit adaptive immunity.

Cancer immunotherapy based on image-guided STING activation by nucleotide nanocomplex-decorated ultrasound microbubbles

Jacques Lux, Ph.D., and his team developed MUSIC (Microbubble-assisted Ultrasound-guided Immunotherapy of Cancer), an innovative technology designed to activate STING in antigen-presenting cells and generate a potent, durable anti-tumor immune response. The approach addresses the clinical limitations of natural STING agonists like cyclic dinucleotides, which suffer from poor cytosolic entry, serum stability, low specificity, and rapid tissue clearance. The team loaded the natural STING agonist cGAMP onto clinically established microbubbles using nanocomplexes composed of cGAMP electrostatically bound to biocompatible branched cationic biopolymers. Application of external ultrasound pulses creates transient pores in antigen-presenting cell membranes through sonoporation, enabling direct cGAMP delivery into the cytosol and resulting in cGAS-STING activation. This targeted local activation leads to enhanced proinflammatory pathways that efficiently prime antigen-specific T cells, bridging innate and adaptive immunity. The technology successfully inhibited tumor growth in both localized and metastatic murine cancer models and improved the therapeutic efficacy of checkpoint blockade, demonstrating the potential for novel image-guided strategies in targeted cancer immunotherapy.