Lymphodepletion, tumor-infiltrating lymphocytes, and high versus low dose IL-2 followed by pembrolizumab in patients with metastatic melanoma

• Published in: Oncoimmunology Vol. 14; no. 1; p. 2546402
• Main Authors: Hasanov, Merve, Kiany, Simin, Forget, Marie-Andrée, Bassett, Roland, Davies, Michael A., Diab, Adi, Gershenwald, Jeffrey E., Glitza, Isabella C., Lee, Jeffrey E., Lucci, Anthony, McQuade, Jennifer L., Patel, Sapna P., Ross, Merrick I., Tawbi, Hussein A., Wargo, Jennifer A., Wong, Michael K., Bernatchez, Chantale, Hwu, Patrick, Haymaker, Cara, Amaria, Rodabe N.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.12.2025; Taylor & Francis Group
• Subjects: adoptive cell therapy; Adult; Aged; anti-PD-1; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; checkpoint blockade; Female; Humans; immune profiling; interleukin 2; Interleukin-2 - administration & dosage; Interleukin-2 - adverse effects; Lymphocyte Depletion - methods; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - transplantation; Male; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Middle Aged; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Treatment Outcome; Tumor-infiltrating lymphocytes; immune profiling; checkpoint blockade; Tumor-infiltrating lymphocytes; interleukin 2; adoptive cell therapy; anti-PD-1
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2025.2546402

This study evaluated the efficacy and safety of unengineered tumor-infiltrating lymphocytes (TILs) combined with pembrolizumab and either high (HD, Arm-1) or low (LD, Arm-2) doses of IL-2 in patients with metastatic melanoma (MM). Patients were lymphodepleted with cyclophosphamide and fludarabine, followed by TIL infusion and IL-2 (Arm-1: 720,000 IU/kg IV q 8 hrs up to 15 doses; Arm-2: 2 million IU SC for 14 days). Patients received pembrolizumab 200 mg IV starting 21 days post-TIL infusion, and every 3 weeks for up to 2 years. The primary endpoint was overall response rate (ORR) per RECIST 1.1. Blood samples were collected for longitudinal flow cytometry and cytokine analysis. In Arm-1 (  = 7), one patient had a partial response (PR) for 10 months, two had stable disease (SD), three had progressive disease (PD), and one was not evaluable (NE). In Arm-2 (  = 7), one patient had an ongoing PR for over 76 months, one had SD, and five had PD. The toxicity profiles were comparable; however, patients in Arm-2 had lower grade 3 febrile neutropenia (57% vs. 71%) and shorter hospitalization (median 16 days vs. 18 days). No correlation was observed between TIL phenotype and clinical response, although PR patients received high numbers of TIL with a high CD8 /CD4 T cell ratio. IL-2 dose did not affect the frequency, phenotype, or proliferation of circulating T cell subsets, and anti-PD-1 did not boost T-cell proliferation. No significant differences were observed between IL-2 doses, suggesting low-dose IL-2 as an alternative to high-dose IL-2 after TIL administration.