在葡萄膜黑色素瘤伴肝转移患者中通过肝动脉输注局部给予肿瘤浸润淋巴细胞

Background: Cell therapy using autologous tumor infiltrating lymphocytes (TIL) has emerged as an important treatment option in refractory metastatic cutaneous melanoma. Also, in uveal melanoma (UM) TIL therapy has shown clinical efficacy using conventional systemic administration of cells. Based on the prominent liver tropism, we investigated whether TIL administration directly into the liver circulation is feasible, safe and effective. Methods: TILs were manufactured using a semi-automated system (Miltenyi Biotec CliniMACS Prodigy) at the GMP facility, Sahlgrenska University Hospital. An exploratory phase 1 trial was designed with six patients with treatment refractory metastatic UM. Key criteria for participation included histologically confirmed diagnosis of UM, performance status of ECOG 0-2, liver dominant disease and no cardiovascular and pulmonary comorbidity. A dose-escalation regimen of cells was applied, 10^8-10^9, and following angiography, to assess anatomical variation, the TILs were infused over 30 min by hepatic artery infusion (HAI). Lymphodepletion was achieved by melphalan and following HAI the patients received low dose IL-2 subcutaneously for up to 14 days. Primary endpoint was the incidence and severity of adverse events (AE). Secondary endpoints included feasibility by assessing manufacturing and administration of TILs, and clinical efficacy evaluated by FDG/PET-CT using RECIST 1.1 criteria. Results: Eight patients were enrolled in the study. Two patients did not proceed to treatment, one due to the diagnosis of a second malignancy and one due to failure of TIL expansion. Six patients received treatment, all previously treated. TILs were manufactured from surgical biopsies in four patients and from needle biopsies in two patients. Five were treated according to protocol, while one patient received a lower TIL dose than planned. The infused TIL products consisted of CD3⁺ T cells with a variable proportion of CD8⁺ cells (range 1-83%). No AEs related to the HAI procedure were observed. All patients experienced grade ≥3 cytopenias, including anemia, lymphopenia, neutropenia, and thrombocytopenia related to preconditioning melphalan chemotherapy, and two patients experienced grade ≥3 AE attributed to TIL/IL-2. Best overall response was stable disease in all patients. Median progression-free survival was 4.3 months, and median overall survival 14.5 months. An explorative FDG/PET-CT analysis using AI-based algorithms revealed reductions in liver metabolic tumor volume, maximum standardized uptake value, and total lesion glycolysis in one patient at week 6 compared with baseline. Conclusion: Local administration of TILs using HAI to patients with liver metastases of uveal melanoma is feasible and safe. The used regimen appears insufficient to achieve durable clinical efficacy and implies a need for further testing.