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Background Extramammary Paget’s disease (EMPD) is a rare cutaneous adenocarcinoma, typically arising in apocrine gland-rich areas such as the vulva, perineum, and scrotum. The disease is usually confined to the epidermis but may become invasive and metastasize, with poor prognoses in advanced stages. While surgery remains the mainstay of treatment for localized disease, the management of metastatic EMPD lacks consensus. Immunotherapy and cellular therapies are emerging as promising modalities in solid tumors, yet limited data exist in the EMPD context. Adoptive CTL therapy, which involves the ex vivo expansion and activation of autologous T lymphocytes, has shown potential in melanoma, EBV-related cancers, and select solid tumors. 1 2 high-dose radiotherapy (HD-RT) with low-dose RT (LD-RT)safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.3 Here, we present a case demonstrating the successful application of combined HD-RT plus LD-RT radiotherapy and CTL therapy.Methods A 65-year-old male underwent VMAT-based radiotherapy to the cervical lesion (60 Gy in 8 fractions) and IMRT to the pulmonary and mediastinal sites (Left lung lesion: 50 Gy/5F, Mediastinal nodes (Station 5: 45 Gy/15F; Station 4L: 25 Gy/5F (HD-RT) + sequential boost 2 Gy/4 (LD-RT) respectively). Concurrently, PBMCs were isolated, activated using CD3/CD28/CD2 stimulants, expanded with IL-2 (1000 IU/mL), and re-infused following a 13-day GMP-compliant expansion protocol.CTLs were infused concurrently with the LD-RT phase duing lung and mediastinal radiation therapy.Results Follow-up PET/CT (3 days post-RT completion) showed: Left neck lesion decreased in size (from 5.2 to 4.0 cm) and SUVmax (16.6 → 13.6); Mediastinal lymph nodes reduced in size and activity (SUVmax 9.7 → 6.0); Left lung lesion decreased (SUVmax 12.1 → 7.3) Right lung nodule stable (SUVmax 2.4 unchanged) ( figure 1). Treatment resulted in partial metabolic response (PMR/PR). The patient experienced no major adverse effects and remained clinically stable.Conclusions This case highlights the potential benefit of combining radiotherapy with adoptive CTL therapy in metastatic EMPD. The rationale includes immune modulation by radiotherapy, enhancing T cell trafficking and tumor antigen release. While single-agent immune checkpoint inhibitors have demonstrated limited activity in EMPD, cell therapy may bypass tumor-induced immunosuppression. Further evaluation in a structured case series or early-phase clinical trial is justified.References Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348(6230):62-68.Chapuis AG, Ragnarsson GB, Nguyen HN, et al. Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype. Proc Natl Acad Sci USA. 2012;109(12):4592-4597.Patel RR, He K, Barsoumian HB, Chang JY, Tang C, Verma V, Comeaux N, Chun SG, Gandhi S, Truong MT, Erasmus JJ, Hong DS, Lee PP, Ning MS, Nguyen QN, Heymach JV, Altan M, Blumenschein G, Fossella FV, Sezen D, Chen D, Carter BW, Davies MA, Glitza IC, Diab A, Ferrarotto R, Cabanillas ME, Yuan Y, Shah SJ, Parra ER, Sun B, Cortez MA, Welsh JW. High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial. Radiother Oncol. 2021 Sep;162:60-67. doi: 10.1016/j.radonc.2021.06.037. Epub 2021 Jul 5.Abstract 679 Figure 1PET/CT pre treatment and 3 days post treatment