Microbubble augmentation of immunotherapy in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is the 7th most common cancer and carries a poor prognosis, with a 5-year survival rate of 55%. Most patients undergo a combination of surgery, radiation, and/or systemic therapy. Recent landmark trials demonstrated therapeutic benefit and acceptable tolerability of anti-programmed death-1 (aPD1) immune checkpoint inhibition resulting in FDA approval and rapid integration into treatment regimens. Neoadjuvant immunotherapy (nICI) aims to boost tumor response rates prior to development of treatment resistance. However, only 20-30% of HNSCC patients demonstrate pathologic treatment response at time of surgery, indicating further augmentation strategies are needed to improve clinical outcomes. Contrast-enhanced ultrasound (CEUS) relies on intravenous microbubble injection and quantification of enhancement kinetics can predict response to therapy. Another unique property of CEUS is its ability to generate stable or inertial microbubble cavitation using localized ultrasound pulses (albeit still well within FDA limits of ultrasound outputs). Importantly, microbubble cavitation has been shown to generate localized bioeffects which can temporarily alter cellular and vascular permeability in tumors. Our group has recently demonstrated the safety and efficacy of using these bioeffects for therapy augmentation in randomized controlled trials in liver cancer radiotherapy and pancreatic cancer chemotherapy. Additionally, recent preclinical data from our group and others has demonstrated the potential of using microbubble cavitation to improve aPD1 therapy in HNSCC models. Consequently, this study aims to demonstrate the feasibility and preliminary efficacy of microbubble- augmented neoadjuvant aPD1 in HNSCC, while also developing quantitative imaging biomarkers to predict treatment response. In the first specific aim, we will evaluate the safety and preliminary efficacy of microbubble cavitation to augment neoadjuvant aPD1 therapy in operable HPV- HNSCC patients. We will perform a phase I/II neoadjuvant study of aPD1 combined with microbubble therapy in up to 39 patients with treatment naïve HNSCC visible on ultrasound. Microbubble sensitization will be performed approximately one hour following each of two aPD1 infusions given every 3 weeks in a 6 week preoperative window. The primary endpoint will be pathologic treatment response as measured by the fraction of patients with at least 50% pathologic treatment effect (pTR2). In the second aim, we will determine the diagnostic performance of quantitative CEUS imaging biomarkers to predict HNSCC pathologic treatment response. Quantitative CEUS data will be obtained during the microbubble-sensitization sessions described above. Patients will then be stratified by treatment response and imaging data compared across response groups. Project Number: 1R21CA303372-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: John Eisenbrey (+1 co-PI) | Institution: THOMAS JEFFERSON UNIVERSITY, PHILADELPHIA, PA | Award Amount: $401,115 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 ISB-V (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11361814