Influence of tumor infiltrating lymphocytes (TIL) monotherapy on persistent clinical and immunological responses in Asian metastatic melanoma patients with specific CD8+ TIL proportions: A phase I trial.

9548 Background: TIL therapy, as one of the most promising adaptive cellular immunotherapy, has shown success in metastatic melanoma, with a median overall response rate (ORR) of 28% and median PFS (progression free survival) of 7.2 months. This phase I clinical trial aimed to explore the safety, feasibility, and efficacy of TILs monotherapy in Asian metastatic melanoma pts. Methods: Pts with metastatic melanoma who had progressed on standard therapies, had both resectable and measurable tumors were eligible to be enrolled. Pts received a lymphodepletion regimen which consisted of cyclophosphamide (30mg/kg) for 2 days, followed by Fludarabine (25mg/m 2 ) for 5 days, approximately 24 hours before receiving the intravenous autologous LM103 (TILs) infusion and then high dose IL-2 for 6 doses (200000IU/Kg, 1 dose per day. Doses can be adjusted based on pts tolerance to support T cell survival and proliferation. Results: Twelve pts (aged 26-68 yrs) with metastatic melanoma were enrolled and treated, including 8 males. Among the primary melanoma types, 6 were acral, 3 mucosal, 2 unknown, and 1 cutaneous. 7 pts had distant organ metastases. As of Jan 2025, 8 out of 12 pts were assessable, one could not be evaluated due to rapid brain metastases and 3 remained under safety observation (median follow-up, 6 wks; range, 2-48 wks). Resected tumors used for TIL production were from 8 metastatic lymph nodes and 4 subcutaneous nodules. The infused autologous TIL contained 8.24-19.47X10 10 viable cells. The median duration of IL-2 infusion were 5.08 days, with a median dose of 13.75 IU/Kg/day. The most frequent treatment-emergent adverse events (TEAEs) were myelosuppression (100%), fever (100%), anemia (100%), and hypotension (100%). Grade 3-4 TEAEs included neutropenia (100%), lymphopenia (100%), leukopenia (100%), fever (75%), thrombocytopenia (62.5%), and anemia. The ORR was 50% (4/8, 4PR, 2SD, 2PD) per RECIST v1.1. The median PFS was not reached and the longest PFS was 11.4 months. Responders demonstrated a larger number of T cell clones, higher T cell receptor (TCR) diversity (Inverse Simpson Index), and lower TCR clonality compared to non-responders ( P =0.031, P=0.049 and P=0.033 ), based on real time peripheral monocytes analysis. These findings suggest that the LM103 in responders recognized a broader antigen spectrum . Notably, about 50% of initial TCR clones can be detected 18 wks post-infusion, suggesting LM103 persistence. Post-hoc analysis revealed that responders had a CD8+ T-cells proportion of 60-80%, while non-responders exhibited extreme proportions (<10% or >80%). Conclusions: LM103 was well tolerated and demonstrated durable responses in Asian patients with advanced melanoma. Patients with 60-80% CD8+T-cell proportions are more likely to respond to TIL therapy. Clinical trial information: CTR20233999 .