Abstract 4318: Combined Quad Shot regimen and immunotherapy for incurable recurrent or metastatic head and neck cancer

Abstract Background: Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) presents significant therapeutic challenges. Current first-line regimens based on PD-1 inhibitors, either as monotherapy or combined with chemotherapy, demonstrate limited efficacy with objective response rates (ORR) of only 20-40% and median overall survival below 15 months. While the theoretical synergy between radiotherapy and immunotherapy is well-established and has been validated across various malignancies, this promising combination has yet to demonstrate breakthrough success in HNSCC clinical practice. This study investigates the potential of a cyclical hypofractionated palliative radiotherapy regimen (QUAD SHOT) to reverse immunotherapy resistance in R/M HNSCC. Methods: We administered palliative Quad Shot radiotherapy to 20 R/M HNSCC patients who had stable disease or progressive disease after two cycles of chemotherapy combined with immunotherapy. These patients received Quad Shot regimen (3.5 Gy twice daily over 2 consecutive days at 4 week intervals per cycle) while maintaining their original systemic treatment. Additionally, in mouse subcutaneous transplantation and spontaneous tumor models, we compared the anti-tumor efficacy of Quad Shot radiotherapy combined with anti-PD-1 antibody versus conventional continuous radiotherapy. Comprehensive immune monitoring utilizing single-cell RNA sequencing and flow cytometry was employed to characterize changes in the tumor microenvironment and tumor-draining lymph nodes. Results: Clinical observations revealed that the irradiated lesions in these treatment-resistant patients achieved an ORR of 85% (17/20) following Quad Shot integration, including complete response in 25% (5/20) and partial response in 60% (12/20) of cases. In preclinical models, the Quad Shot regimen demonstrated superior tumor control and survival outcomes compared to conventional radiotherapy. Mechanistic investigations elucidated that the cyclic radiotherapy schedule effectively prevents the transition from immune activation to immunosuppression typically observed after continuous radiotherapy. This modality facilitates periodic clearance of terminally exhausted CD8+ T cells within the tumor microenvironment while promoting expansion of T progenitor exhausted (Tpex) cells in draining lymph nodes, thereby enabling replenishment of the intratumoral T-cell repertoire. Conclusions: The Quad Shot radiotherapy regimen represents a promising strategy for reversing immunotherapy resistance in R/M HNSCC. The core mechanism involves the cyclic radiotherapy pattern reshaping the tumor immune microenvironment, reversing T-cell exhaustion, and promoting the replenishment of stem-like Tpex cells, thereby restoring tumor response to immune checkpoint inhibitors. Citation Format: Xiao Yang, Zheng Yang, Fei Wang, Lingyi Kong, Chao Wan, Kunyu Yang, . Combined Quad Shot regimen and immunotherapy for incurable recurrent or metastatic head and neck cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4318.