Multimodal PET Defines a 'Goldilocks' Thermal Window for Focused Ultrasound Ablation and Immunotherapy Combinations

Area of Science:

• Oncology
• Medical Imaging
• Biotechnology

Background:

• Thermally ablative focused ultrasound (T-FUS) is a noninvasive method for tumor destruction, with potential to enhance immunotherapy efficacy.
• Optimal T-FUS parameters balancing tumor debulking and preserving local biology for immunotherapy penetration remain unclear.
• Thermal dose is critical for T-FUS efficacy, influencing vascular/stromal features and immunotherapy access.

Purpose of the Study:

• To define a "Goldilocks Zone" for T-FUS thermal dose that balances tumor debulking with immunotherapy delivery.
• To investigate the impact of varying thermal doses on tumor architecture, perfusion, and subsequent antibody penetration.
• To establish a PET-informed framework for optimizing T-FUS parameters in combination with immunotherapy.

Main Methods:

• Three T-FUS thermal dose regimens were applied to 4T1 breast tumors in mice, guided by in silico modeling.
• Tumor ablation, perfusion, microvascular coverage, and hypoxia were assessed using histology, contrast-enhanced ultrasound, and imaging probes.
• Dynamic FDG PET and Zr-89-labeled anti-CD47 immunoPET were used to evaluate tumor metabolism and antibody penetration post-T-FUS.

Main Results:

• Distinct thermal dose profiles resulted in dose-dependent and dose-divergent biological effects.
• An intermediate thermal dose achieved significant tumor debulking, hypoxia relief, and preserved tumor physiology for antibody access.
• PET imaging demonstrated reduced tumor metabolism and approximately 3-fold enrichment of antibody within the residual tumor niche after optimized T-FUS.

Conclusions:

• Thermal dose is a critical factor in T-FUS immunotherapy combinations.
• T-FUS can be tuned to create a post-ablation tumor state permissive to large biologic drug delivery.
• This PET-informed approach provides guidance for tailoring T-FUS regimens to enhance combination cancer therapy.