Safety, tolerance, and preliminary efficacy of autologous tumor-infiltrating lymphocytes (TILs) LM103 injection in Chinese patients with advanced melanoma and an exploration of the factors influencing the therapeutic effect.

Abstract

e21508 Background: The safety and efficacy of TIL in Asian patients, mainly with acral subtypes, remain largely unknown. Therefore, we designed and implemented a clinical trial for Chinese melanoma patients to investigate the safety and effectiveness of TIL (LM103) in treating advanced melanoma. Meanwhile, single-cell RNA sequencing of tumor tissues, TIL injection solution and PBMCs at 12 weeks after injection was conducted to explore the factors that may affect the efficacy of TIL therapy. Methods: Patients with advanced or unresectable melanoma who failed standard treatment were eligible for surgical TIL collection. All patients received a lymphodepletion regimen, including cyclophosphamide at 30 mg/kg days-7 and day-6 and fludarabine 25 mg/m2 days-5 through day-1, followed by infusion of pooled ex-vivo expanded TIL. Patients received high dose IL-2 after TIL infusion. The primary endpoint was safety, and secondary endpoints evaluated by objective response rate (ORR) and disease control rate (DCR) using RECIST 1.1 criteria at 12 weeks. Additionally, to explore the factors influencing the efficacy of TIL treatment, single-cell sequencing was performed on patients' tumor tissues, TIL infusion products, and PBMCs at 12 weeks. The changes in immune environment characteristics and their relationship with efficacy were comprehensively analyzed. Results: A total of 4 patients received TIL treatment, including 3 cases of acral subtype and 1 case of cutaneous subtype melanoma. Median age was 56 (range 42-72) and 75% were female. The median number of TIL infused was 4.5×10 10 (range 3×10 10 - 12×10 10 ). At the 12-week efficacy assessment after TIL treatment, 2 patient was evaluated as having a partial response (PR), 1 patients had stable disease (SD), and 1 patient had progressive disease (PD). Objective response rate (ORR) was 50%, and the disease control rate (DCR) was 75%. Adverse reactions were mainly bone marrow suppression and fever, which were related to lymphodepletion and high-dose IL-2 infusion. The TIL immune cell composition of patients with PD was mainly characterized by a large number of CD8+ T cells in the terminal exhaustion state (Tex term ), while the two patients with PR were characterized by a large number of effector (Tex eff ) and intermediate (Tex int ) exhausted CD8+ T cells and follicular helper T cells (Tfh). Intermediate exhausted CD8+ T cells were the most active type in immune cell communication and had the strongest interaction with Tfh. Conclusions: TIL therapy has demonstrated good safety and tolerability in Chinese patients with advanced melanoma and achieved objective therapeutic effects. The efficacy of TIL treatment may be closely related to the state of immune cells in the TIL infusion, with intermediate CD8+ T cells and Tfh cells being particularly crucial. Clinical trial information: 06697665 .