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BackgroundUveal melanoma (UM) is a rare eye cancer that frequently metastasizes to the liver and responds poorly to current immune and targeted therapies. We previously reported that adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) could achieve a 35% objective response rate (ORR) in metastatic UM (NCT01814046).1 The infusion product potency, based upon autologous anti-tumor reactivity, was the strongest correlate of response. Here, we present interim results from a follow-up phase 2 trial designed to validate these findings and prospectively evaluate predictors of response.MethodsIn this single-center phase 2 trial (NCT03467516), metastatic UM patients underwent metastatectomy to generate early TIL cultures. Cultures demonstrating autologous anti-tumor reactivity and growth potential were expanded for infusion. Patients received non-myeloablative lymphodepletion with cyclophosphamide and fludarabine, followed by infusion of TIL and high-dose interleukin-2. The primary endpoint was ORR using RECIST v1.1. Exploratory analyses included pooled comparison of TIL potency versus clinical response from both NCT03467516 and NCT01814046, along with transcriptomic analysis of source metastases using a recently defined in situ tumor biomarker (UMIS).2 ResultsAs of June 2, 2025, 31 UM patients received TIL therapy. Most had high disease burden: 81% stage M1b/M1c, 77% with elevated LDH, and 71% had both hepatic and extrahepatic metastases. The median number of prior metastatic therapies was two, including checkpoint blockade in 61% and tebentafusp in 32% of patients. Liver metastases were the most common TIL source (52%). Infusion products contained a median of 5.24×101 0 TIL, were predominantly CD8+ (median 61%), and demonstrated autologous anti-tumor reactivity in 62%. Among 30 evaluable patients, the initial overall ORR was 33% (10/30), with a confirmed ORR (cORR) of 20% (6/30) at the time of reporting. Median duration of confirmed responses was 10.8 months (longest ongoing at 52 months). Pre-planned immunologic analysis found infusion of tumor-reactive TIL yielded a cORR of 33% (6/18), compared to 0% (0/11) with nonreactive products (figures 1 and 2). Further, in the pooled cohort (n=46), infusion of tumor-reactive TIL demonstrated significantly higher cORR of 41% (11/27) versus 0% (0/19) with nonreactive products (P=0.001). UMIS transcriptomic profiling of source metastases predicted early TIL reactivity (n=50; P<0.0001) and clinical response (n=48; P=0.008).ConclusionsThis study confirms that TIL therapy has efficacy against highly advanced and pretreated metastatic UM. TIL potency, defined by autologous anti-tumor reactivity, was the strongest predictor of response. Integration of transcriptomic biomarkers such as UMIS to identify metastases harboring potent TIL may optimize patient selection and improve outcomes.AcknowledgementsAldesleukin was provided by Clinigen Limited and Iovance Biotherapeutics.Trial RegistrationNCT03467516ReferencesChandran SS, Somerville RPT, Yang JC, Sherry RM, Klebanoff CA, Goff SL, et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 2017;18(6):792–802.Leonard-Murali S, Bhaskarla C, Yadav GS, Maurya SK, Galiveti CR, Tobin JA, et al. Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility. Nat Commun. 2024;15(1):2863.Ethics ApprovalPatients gave informed consent prior to trial participation in accordance with the Declaration of Helsinki. This trial was reviewed and approved by the University of Pittsburgh Institutional Review Board (Approval CR19110103-018).Abstract 598 Figure 1Waterfall plot of clinical responses in patients with metastatic uveal melanoma after TIL therapy (NCT03467516)[Image Omitted. See PDF.]Abstract 598 Figure 2Spider plot of clinical responses in patients with metastatic uveal melanoma after TIL therapy (NCT03467516)[Image Omitted. See PDF.]