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Background Squamous cell carcinoma of the head and neck (HNSCC) is a common malignancy that claims many lives each year worldwide. The entity may be associated with tobacco use and infection with carcinogenic strains of human papillomavirus. 1 Carcinogenesis occurs on mucosal surfaces, with clinical presentation typically occurring relatively late in the disease process, accounting for the high rate of recurrence and metastasis.2 Metastasis typically progresses down the cervical lymphatics and may encase and invade critical structures, such as the carotid arteries. Currently, standard of care involves surgery, chemotherapy, and radiation, with emerging treatment options including systemic targeted agents and immunotherapies.3 HNSCC presents an attractive target for immunotherapy given the relatively high tumor mutational burden.4 5 Traditional treatment options and systemic immunotherapy may carry significant morbidity. We present a novel treatment regimen with pulsed electrical field ablation combined with intra-tumoral immunotherapy injection.Methods Treatments were performed using computed tomography guidance in a percutaneous fashion. Pulsed electrical field ablation was performed within the tumor for 4 cycles using the Aliya pulsed electrical field system (Galvanize, Redwood City, California, United States). After ablation was performed, the immunotherapy mixture was administered into the tumor, mixed with iodinated contrast for visibility and gelfoam slurry for local retention.Results AR is a 60-year-old male who presented with a fluorodeoxyglucose avid soft tissue mass centered on the right maxillary sinus which measured 4.8 cm x 6.0 cm in maximum axial dimension ( figure 1). Biopsy was positive for squamous cell carcinoma. The mass was disfiguring and there was right orbital involvement. He received four treatments with intra-tumoral immunotherapy injection. The first treatment session included four cycles of pulsed electrical field ablation. Subsequent treatments performed at week 3 and week 4 were limited to intra-tumoral immunotherapy injection. An additional intra-tumoral immunotherapy injection was performed at the 8-month timepoint. Tumor regression was noted at that time on intra-procedural computed tomography. At 14 months follow up, the patient achieved a substantial radiologic response with marked immunologic tumor elimination (figure 2). Clinically, the bulky, disfiguring mass is resolved at 22 months. Additional follow-up imaging is pending at this time. The patient suffered no treatment-related toxicity or procedural complication.Conclusions Pulsed electrical field ablation plus intra-tumoral immunotherapy is safe and effective for treatment of head and neck squamous cell carcinoma.References Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. Nov 26 2020;6(1):92.Chen SMY, Krinsky AL, Woolaver RA, Wang X, Chen Z, Wang JH. Tumor immune microenvironment in head and neck cancers. Mol Carcinog. Jul 2020;59(7):766-774.Ghosh S, Shah PA, Johnson FM. Novel systemic treatment modalities including immunotherapy and molecular targeted therapy for recurrent and metastatic head and neck squamous cell carcinoma. Int J Mol Sci. Jul 17 2022;23(14).Gabbia D, De Martin S. Tumor mutational burden for predicting prognosis and therapy outcome of hepatocellular carcinoma. Int J Mol Sci. Feb 08 2023;24(4).Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell. Feb 08 2021;39(2):154-173.Abstract 702 Figure 1Selected images from F-18 fluorodeoxyglucose PET/CT (left) and postcontrast axial T1 fat-suppressed MRI (right), demonstrate bulky radionuclide avid mass centered on the right maxillary sinus with orbital involvement and calvarial breakthroughAbstract 702 Figure 2Postcontrast axial T1 fat-suppressed images at 14 months follow up. Selected images at the level of the maxillary sinus (left) and orbit (right), demonstrating marked tumor elimination