Tumor-infiltrating lymphocyte (TIL) therapy for immunotherapy-refractory advanced melanoma: a systematic review of response and survival rates
DOI:
https://doi.org/10.56183/iberojhr.v5i2.845Palavras-chave:
Tumor-infiltrating lymphocyte (TIL) therapy, Lifileucel, Advanced melanoma, Immunotherapy resistance, Adoptive cell therapy, Response rates, Survival outcomes.Resumo
Advanced melanoma that progresses after immune checkpoint inhibitors (ICIs) such as anti–PD-1 and anti–CTLA-4 antibodies represents an urgent therapeutic challenge. Tumor-infiltrating lymphocyte (TIL) therapy, an adoptive cell therapy that re-infuses ex vivo–expanded autologous T cells, has shown renewed potential for overcoming immunotherapy resistance. Recent clinical trials, including lifileucel-based regimens, have reported encouraging response and survival outcomes in heavily pretreated populations. This systematic review aimed to evaluate the clinical efficacy, survival outcomes, safety, and feasibility of TIL therapy in patients with immunotherapy-refractory advanced melanoma. A comprehensive search was conducted across PubMed, Scopus, and Google Scholar for studies published between 2014 and 2025 using the terms tumor-infiltrating lymphocyte therapy, TIL therapy, advanced melanoma, and lifileucel. Eligible studies included phase I–III clinical trials, cohort studies, and systematic reviews reporting response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety outcomes. Across multiple phase II and III studies, lifileucel achieved objective response rates (ORRs) of 31–36% in immunotherapy-refractory cohorts, including complete responses in up to 12% of patients. The median DoR exceeded 36 months, and 31.3% of responders maintained responses at 5 years. Median PFS ranged from 4.1 to 7.2 months, and median OS from 13.9 to 25.8 months, with some patients achieving long-term disease control beyond five years. Predictors of improved response included lower tumor burden and normal LDH levels. TIL therapy exhibited a predictable and manageable safety profile, dominated by transient grade 3/4 hematologic toxicities related to lymphodepletion and IL-2. Manufacturing feasibility was high, with cryopreserved lifileucel products enabling consistent expansion and delivery across treatment centers. Continued research should refine patient selection, optimize production, and evaluate combination strategies to enhance long-term survival and broaden clinical accessibility.
Referências
Boutros, A., Croce, E., Ferrari, M., Gili, R., Massaro, G., Marconcini, R., Arecco, L., Tanda, E. T., & Spagnolo, F. (2024). The treatment of advanced melanoma: Current approaches and new challenges. Critical Reviews in Oncology/Hematology, 196, 104276. https://doi.org/10.1016/J.CRITREVONC.2024.104276
Chen, R., Johnson, J., Rezazadeh, A., & Dudek, A. Z. (2025). Tumour-infiltrating lymphocyte therapy landscape: prospects and challenges. BMJ Oncology, 4(1), e000566. https://doi.org/10.1136/BMJONC-2024-000566
Chesney, J., Lewis, K. D., Kluger, H., Hamid, O., Whitman, E., Thomas, S., Wermke, M., Cusnir, M., Domingo-Musibay, E., Phan, G. Q., Kirkwood, J. M., Hassel, J. C., Orloff, M., Larkin, J., Weber, J., Furness, A. J. S., Khushalani, N. I., Medina, T., Egger, M. E., … Sarnaik, A. (2022). Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. Journal for Immunotherapy of Cancer, 10(12). https://doi.org/10.1136/JITC-2022-005755
Ferris, R. L., Leidner, R. S., Chung, C. H., Jimeno, A., Lee, S. M., Sukari, A., Nieva, J. J., Grilley-Olson, J. E., Redman, R., Wong, S. J., Villaflor, V. M., Misleh, J., Finckenstein, F. G., Chou, J., Gastman, B., Fiaz, R., Catlett, M., Yi, M., & Cohen, E. E. W. (2025). Efficacy and safety of one-time autologous tumor-infiltrating lymphocyte cell therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Journal for Immunotherapy of Cancer, 13(8), e011633. https://doi.org/10.1136/JITC-2025-011633
Knight, A., Karapetyan, L., & Kirkwood, J. M. (2023). Immunotherapy in Melanoma: Recent Advances and Future Directions. Cancers, 15(4), 1106. https://doi.org/10.3390/CANCERS15041106
Martín-Lluesma, S., Svane, I. M., Dafni, U., Vervita, K., Karlis, D., Dimopoulou, G., Tsourti, Z., Rohaan, M. W., Haanen, J. B. A. G., & Coukos, G. (2024). Efficacy of TIL therapy in advanced cutaneous melanoma in the current immuno-oncology era: updated systematic review and meta-analysis. Annals of Oncology, 35(10), 860–872. https://doi.org/10.1016/j.annonc.2024.07.723
Matsueda, S., Chen, L., Li, H., Yao, H., & Yu, F. (2024). Recent clinical researches and technological development in TIL therapy. Cancer Immunology, Immunotherapy, 73(11), 1–20. https://doi.org/10.1007/S00262-024-03793-4/FIGURES/2
Medina, T., Chesney, J. A., Kluger, H. M., Hamid, O., Whitman, E. D., Cusnir, M., Thomas, S. S., Wermke, M., Domingo-Musibay, E., Phan, G. Q., Kirkwood, J. M., Larkin, J., Weber, J., Finckenstein, F. G., Chou, J., Gastman, B., Wu, X., Fiaz, R., & Sarnaik, A. A. (2025). Long-term Efficacy and Safety of Lifileucel Tumor-infiltrating Lymphocyte (TIL) Cell Therapy in Patients with Advanced Melanoma: A 5-year Analysis of the C-144-01 Study. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. https://doi.org/10.1200/JCO-25-00765
Navarro Rodrigo, B., Ortiz Miranda, Y., Corria-Osorio, J., Coukos, G., & Harari, A. (2025). Immune correlates and mechanisms of TIL therapy efficacy: current insights and knowledge gaps. Trends in Cancer. https://doi.org/10.1016/J.TRECAN.2025.08.002
Rohaan, M. W., Borch, T. H., Berg, J. H. van den, Met, Ö., Kessels, R., Foppen, M. H. G., Granhøj, J. S., Nuijen, B., Nijenhuis, C., Jedema, I., Zon, M. van, Scheij, S., Beijnen, J. H., Hansen, M., Voermans, C., Noringriis, I. M., Monberg, T. J., Holmstroem, R. B., Wever, L. D. V., … Haanen, J. B. A. G. (2022). Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. New England Journal of Medicine, 387(23), 2113–2125. https://doi.org/10.1056/NEJMOA2210233
Sarnaik, A. A., Hamid, O., Khushalani, N. I., Lewis, K. D., Medina, T., Kluger, H. M., Thomas, S. S., Domingo-Musibay, E., Pavlick, A. C., Whitman, E. D., Martin-Algarra, S., Corrie, P., Curti, B. D., Oláh, J., Lutzky, J., Weber, J. S., Larkin, J. M. G., Shi, W., Takamura, T., … Chesney, J. A. (2021). Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 39(24), 2656–2666. https://doi.org/10.1200/JCO.21.00612
Shoushtari, A. N., & Powell, D. J. (2025). Tumor-Infiltrating Lymphocyte Therapy for Melanoma and Other Solid Tumors: Looking Back, Yet Moving Forward. Transplantation and Cellular Therapy, 31(3), S581–S590. https://doi.org/10.1016/j.jtct.2024.11.017
Shui, I. M., Scherrer, E., Frederickson, A., Li, J. W., Mynzhassarova, A., Druyts, E., & Tawbi, H. (2022). Resistance to anti-PD1 therapies in patients with advanced melanoma: systematic literature review and application of the Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce anti-PD1 resistance definitions. Melanoma Research, 32(6), 393–404. https://doi.org/10.1097/CMR.0000000000000850
Smithy, J. W., Schoenfeld, A. J., & Betof Warner, A. (2025). The Clinical TIL Experience in Melanoma: Past, Present, Future. Transplantation and Cellular Therapy, 31(3), S626–S634. https://doi.org/10.1016/J.JTCT.2024.11.013
Sorino, C., Iezzi, S., Ciuffreda, L., & Falcone, I. (2024). Immunotherapy in melanoma: advances, pitfalls, and future perspectives. Frontiers in Molecular Biosciences, 11, 1403021. https://doi.org/10.3389/FMOLB.2024.1403021
Tsai, K. K., & Komanduri, K. V. (2025). Tumor-Infiltrating Lymphocyte Therapy for the Treatment of Metastatic Melanoma. American Journal of Clinical Dermatology, 26(5), 733. https://doi.org/10.1007/S40257-025-00957-5
Turcotte, S., Donia, M., Gastman, B., Besser, M., Brown, R., Coukos, G., Creelan, B., Mullinax, J., Sondak, V. K., Yang, J. C., Rohaan, M. W., Marie Svane, I., Lotze, M. T., Haanen, J. B. A. G., & Goff, S. L. (2025). Art of TIL immunotherapy: SITC’s perspective on demystifying a complex treatment. Journal for Immunotherapy of Cancer, 13(1), e010207. https://doi.org/10.1136/JITC-2024-010207
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Copyright (c) 2025 Lesli Ivett Jimenez Garcia, Samira Dayuma Asquel Caiza, Erika Isabel Rogel Macas, Andres Felipe Santodomingo Galindo, Gabriel Eduardo Dede Badillo, Armando Nolasco Toledo
Este trabalho está licenciado sob uma licença Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
