Comparing the Efficacy and Safety of Tumor-Infiltrating Lymphocyte Therapy and Pembrolizumab in Advanced Melanoma: A Randomized Controlled Trial
,
Abstract
TIL and pembrolizumab treatments compared for advanced melanoma patient outcomes. The idea was to determine which one was better, the safety of each, and the quality of life of the patients under the treatments. While understanding the safety profile of both drugs, the assumption was that TIL therapy would be a better alternative to pembrolizumab in survival outcomes and quality of life improvements. 120 patients were randomly allocated (TIL n=60; pembrolizumab n=60). Progression-free survival (PFS) and overall survival (OS) were taken as primary endpoints. Secondary endpoints were objective response rate (ORR), quality of life (EORTC QLQ-C15-PAL), and safety (CTCAE v5.0). Median PFS was 8 vs 6 months (HR=0.85, 95% CI: 0.65-1.12; P=0.15). Median OS was 18 vs 17 months (HR=0.92, 95% CI: 0.70-1.21; P=0.21). ORR was similar (36% vs 34%). TIL improved physical functioning, and both arms provided emotional benefit. TIL was associated with higher rates of grade 3-4 toxicities, including neutropenia and cytokine release syndrome. TIL therapy resulted in survival outcomes similar to those with pembrolizumab, with improved quality of life but higher toxicity.
1. Khammari A, Nguyen J, Leccia MT, Guillot B. Tumor infiltrating lymphocytes as adjuvant treatment in stage III melanoma patients with one invaded lymph node after complete resection. Cancer Immunol Immunother 2020;69:2041-52.
2. Uryvaev A, Passhak M, Hershkovits D, Sabo E. Tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in metastatic NSCLC or melanoma. Med Oncol 2018;35:108.
3. Sarnaik AA, Hamid O, Khushalani NI. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol 2021;39:2656-66.
4. Barras D, Ghisoni E, Chiffelle J, Orcurto A. Response to TIL adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma. Sci Immunol 2024;9:eadi7995.
5. Chesney J, Lewis K, Kluger H. Tumor-infiltrating lymphocyte cell therapy in advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies. J Immunother Cancer 2022;10:e005678.
6. Fu Q, Chen N, Ge C, Li R, Li Z, Zeng B, Li C. Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis. Oncol Immunol 2019;8:1593806.
7. Hall M, Mullinax J, Cox C, Hall A. Combination nivolumab, CD137 agonism, and TIL adoptive cell therapy for metastatic melanoma. Clin Cancer Res 2022;28:5317-27.
8. Hirai I, Funakoshi T, Kamijuku H, Fukuda K. Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to checkpoint inhibitors. Cancer Sci 2021;112:2282-91.
9. Hulen T, Chamberlain C, Svane IM, Met Ö. ACT up TIL now: the evolution of TILs in adoptive cell therapy for solid tumors. Immuno 2021;1:282-96.
10. Granhøj JS, Jensen P. Tumor-infiltrating lymphocytes for adoptive cell therapy: recent advances, challenges, and future directions. Expert Opin Biol Ther 2022;22:697-708.
11. Kristensen N, Heeke C, Tvingsholm SA, Borch A. Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive TIL therapy in melanoma. J Clin Invest 2022;132:e150535.
12. Lindenberg M, Retèl VP, van den Berg JH. Treatment with TILs in advanced melanoma: evaluation of early clinical implementation of an advanced therapy medicinal product. Immunotherapy 2018;10:889-98.
13. Antohe M, Nedelcu R, Nichita L. Tumor infiltrating lymphocytes: the regulator of melanoma evolution. Oncol Lett 2019;17:4155-61.
14. Saint-Jean M, Knol AC, Volteau C. Adoptive cell therapy with TILs in advanced melanoma patients. J Immunol Res 2018;2018:3530148.
15. Maibach F, Sadozai H, Jafari SS. Tumor-infiltrating lymphocytes and their prognostic value in cutaneous melanoma. Front Immunol 2020;11:2105.
16. Markovic S, Galli F, Suman V, Nevala W. Non-invasive visualization of TILs in metastatic melanoma patients on checkpoint inhibitor therapy: a pilot study. J Immunother Cancer 2018;6:65.
17. Mehta G, Malekzadeh P, Shelton T. Outcomes of adoptive cell transfer with TILs for metastatic melanoma with and without brain metastases. Immunotherapy 2018;10:819-29.
18. Fradley MG, Damrongwatanasuk R. Cardiovascular toxicity and mortality associated with adoptive cell therapy and TILs for advanced melanoma. Immunotherapy 2021;13:95-107.
19. Mullinax J, Hall M, Prabhakaran S, Weber J. Combination of pembrolizumab and TIL adoptive cell therapy for metastatic melanoma. Front Oncol 2018;8:44.
20. Rohaan MW, Borch T, van den Berg JH, Kvistborg P. TIL therapy or pembrolizumab in advanced melanoma. N Engl J Med 2022;387:2345-57.
21. Rohaan MW, van den Berg JH, Kvistborg P. Adoptive transfer of TILs in melanoma: a viable treatment option. J Immunother Cancer 2018;6:102.
22. Nguyen L, Saibil SD, Sotov V, Le M, Khoja L. Phase II trial of adoptive cell therapy with autologous TILs and low-dose IL-2 in metastatic melanoma. Cancer Immunol Immunother 2019;68:773-85.
23. Pillai M, Jiang Y, Lorigan P. Clinical feasibility and outcomes with nonselected autologous TIL therapy in advanced cutaneous melanoma. Am J Clin Oncol 2022;45:355-63.
24. Klobuch S, Seijkens TTP, Schumacher T. TIL therapy for patients with advanced-stage melanoma. Nat Rev Clin Oncol 2024;21:157-70.
25. Seitter S, Sherry R, Yang J, Robbins P. Impact of prior treatment on efficacy of adoptive transfer of TILs in metastatic melanoma. Clin Cancer Res 2021;27:5289-98.
26. Dafni U, Michielin O, Lluesma SM, Tsourti Z. Efficacy of adoptive TIL therapy with recombinant IL-2 in advanced cutaneous melanoma: systematic review and meta-analysis. Ann Oncol 2019;30:1902-10.
27. van den Berg JH, Heemskerk B. TIL therapy in metastatic melanoma: boosting of neoantigen-specific T-cell reactivity and long-term follow-up. J Immunother Cancer 2020;8:e001050.
28. Warner AB, Corrie P, Hamid O. TIL therapy in melanoma: facts to the future. Clin Cancer Res 2023;29:1835-44.
29. Zhao Y, Deng J, Rao S, Guo S, Shen J, Du F, Wu X. TIL therapy for solid tumor treatment: progress and challenges. Cancers (Basel) 2022;14:4160.
30. Martín-Lluesma S, Svane IM, Dafni U, Vervita K, Karlis D, Dimopoulou G, Tsourti Z, Rohaan MW, Haanen JBAG, Coukos G. Efficacy of TIL therapy in advanced cutaneous melanoma in the current immuno-oncology era: updated systematic review and meta-analysis. Ann Oncol 2024;35:860-72.
31. Zamani MR, Šácha P. Immune checkpoint inhibitors in cancer therapy: what lies beyond monoclonal antibodies? Med Oncol 2025;42:273.
32. Zippel D, Friedman-Eldar O, Rayman S. Tissue harvesting for adoptive TIL therapy in metastatic melanoma. Anticancer Res 2019;39:4995-5000.
33. Xu H, Huang Y, Zhao N, Hu H, Cao D. Retrospective analysis of pembrolizumab-related adverse reactions and death outcomes based on the FAERS database. BMC Cancer 2025;25:917.
34. Betof Warner A, Hamid O, Komanduri K, Amaria R, Butler MO, Haanen J, Nikiforow S, Puzanov I, Sarnaik A, Bishop MR, Schoenfeld AJ. Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. J Immunother Cancer 2024;12:e008735.
35. Albarrán Fernández V, Ballestín Martínez P, Stoltenborg Granhøj J, Borch TH, Donia M, Marie Svane I. Biomarkers for response to TIL therapy: a comprehensive review. J Immunother Cancer 2024;12:e008640
2. Uryvaev A, Passhak M, Hershkovits D, Sabo E. Tumor-infiltrating lymphocytes (TILs) as a predictive biomarker of response to anti-PD1 therapy in metastatic NSCLC or melanoma. Med Oncol 2018;35:108.
3. Sarnaik AA, Hamid O, Khushalani NI. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol 2021;39:2656-66.
4. Barras D, Ghisoni E, Chiffelle J, Orcurto A. Response to TIL adoptive therapy is associated with preexisting CD8+ T-myeloid cell networks in melanoma. Sci Immunol 2024;9:eadi7995.
5. Chesney J, Lewis K, Kluger H. Tumor-infiltrating lymphocyte cell therapy in advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies. J Immunother Cancer 2022;10:e005678.
6. Fu Q, Chen N, Ge C, Li R, Li Z, Zeng B, Li C. Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis. Oncol Immunol 2019;8:1593806.
7. Hall M, Mullinax J, Cox C, Hall A. Combination nivolumab, CD137 agonism, and TIL adoptive cell therapy for metastatic melanoma. Clin Cancer Res 2022;28:5317-27.
8. Hirai I, Funakoshi T, Kamijuku H, Fukuda K. Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to checkpoint inhibitors. Cancer Sci 2021;112:2282-91.
9. Hulen T, Chamberlain C, Svane IM, Met Ö. ACT up TIL now: the evolution of TILs in adoptive cell therapy for solid tumors. Immuno 2021;1:282-96.
10. Granhøj JS, Jensen P. Tumor-infiltrating lymphocytes for adoptive cell therapy: recent advances, challenges, and future directions. Expert Opin Biol Ther 2022;22:697-708.
11. Kristensen N, Heeke C, Tvingsholm SA, Borch A. Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive TIL therapy in melanoma. J Clin Invest 2022;132:e150535.
12. Lindenberg M, Retèl VP, van den Berg JH. Treatment with TILs in advanced melanoma: evaluation of early clinical implementation of an advanced therapy medicinal product. Immunotherapy 2018;10:889-98.
13. Antohe M, Nedelcu R, Nichita L. Tumor infiltrating lymphocytes: the regulator of melanoma evolution. Oncol Lett 2019;17:4155-61.
14. Saint-Jean M, Knol AC, Volteau C. Adoptive cell therapy with TILs in advanced melanoma patients. J Immunol Res 2018;2018:3530148.
15. Maibach F, Sadozai H, Jafari SS. Tumor-infiltrating lymphocytes and their prognostic value in cutaneous melanoma. Front Immunol 2020;11:2105.
16. Markovic S, Galli F, Suman V, Nevala W. Non-invasive visualization of TILs in metastatic melanoma patients on checkpoint inhibitor therapy: a pilot study. J Immunother Cancer 2018;6:65.
17. Mehta G, Malekzadeh P, Shelton T. Outcomes of adoptive cell transfer with TILs for metastatic melanoma with and without brain metastases. Immunotherapy 2018;10:819-29.
18. Fradley MG, Damrongwatanasuk R. Cardiovascular toxicity and mortality associated with adoptive cell therapy and TILs for advanced melanoma. Immunotherapy 2021;13:95-107.
19. Mullinax J, Hall M, Prabhakaran S, Weber J. Combination of pembrolizumab and TIL adoptive cell therapy for metastatic melanoma. Front Oncol 2018;8:44.
20. Rohaan MW, Borch T, van den Berg JH, Kvistborg P. TIL therapy or pembrolizumab in advanced melanoma. N Engl J Med 2022;387:2345-57.
21. Rohaan MW, van den Berg JH, Kvistborg P. Adoptive transfer of TILs in melanoma: a viable treatment option. J Immunother Cancer 2018;6:102.
22. Nguyen L, Saibil SD, Sotov V, Le M, Khoja L. Phase II trial of adoptive cell therapy with autologous TILs and low-dose IL-2 in metastatic melanoma. Cancer Immunol Immunother 2019;68:773-85.
23. Pillai M, Jiang Y, Lorigan P. Clinical feasibility and outcomes with nonselected autologous TIL therapy in advanced cutaneous melanoma. Am J Clin Oncol 2022;45:355-63.
24. Klobuch S, Seijkens TTP, Schumacher T. TIL therapy for patients with advanced-stage melanoma. Nat Rev Clin Oncol 2024;21:157-70.
25. Seitter S, Sherry R, Yang J, Robbins P. Impact of prior treatment on efficacy of adoptive transfer of TILs in metastatic melanoma. Clin Cancer Res 2021;27:5289-98.
26. Dafni U, Michielin O, Lluesma SM, Tsourti Z. Efficacy of adoptive TIL therapy with recombinant IL-2 in advanced cutaneous melanoma: systematic review and meta-analysis. Ann Oncol 2019;30:1902-10.
27. van den Berg JH, Heemskerk B. TIL therapy in metastatic melanoma: boosting of neoantigen-specific T-cell reactivity and long-term follow-up. J Immunother Cancer 2020;8:e001050.
28. Warner AB, Corrie P, Hamid O. TIL therapy in melanoma: facts to the future. Clin Cancer Res 2023;29:1835-44.
29. Zhao Y, Deng J, Rao S, Guo S, Shen J, Du F, Wu X. TIL therapy for solid tumor treatment: progress and challenges. Cancers (Basel) 2022;14:4160.
30. Martín-Lluesma S, Svane IM, Dafni U, Vervita K, Karlis D, Dimopoulou G, Tsourti Z, Rohaan MW, Haanen JBAG, Coukos G. Efficacy of TIL therapy in advanced cutaneous melanoma in the current immuno-oncology era: updated systematic review and meta-analysis. Ann Oncol 2024;35:860-72.
31. Zamani MR, Šácha P. Immune checkpoint inhibitors in cancer therapy: what lies beyond monoclonal antibodies? Med Oncol 2025;42:273.
32. Zippel D, Friedman-Eldar O, Rayman S. Tissue harvesting for adoptive TIL therapy in metastatic melanoma. Anticancer Res 2019;39:4995-5000.
33. Xu H, Huang Y, Zhao N, Hu H, Cao D. Retrospective analysis of pembrolizumab-related adverse reactions and death outcomes based on the FAERS database. BMC Cancer 2025;25:917.
34. Betof Warner A, Hamid O, Komanduri K, Amaria R, Butler MO, Haanen J, Nikiforow S, Puzanov I, Sarnaik A, Bishop MR, Schoenfeld AJ. Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. J Immunother Cancer 2024;12:e008735.
35. Albarrán Fernández V, Ballestín Martínez P, Stoltenborg Granhøj J, Borch TH, Donia M, Marie Svane I. Biomarkers for response to TIL therapy: a comprehensive review. J Immunother Cancer 2024;12:e008640
| Files | ||
| Issue | Vol 63 No 6 (2025) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/acta.v63i6.20681 | |
| Keywords | ||
| Melanoma Tumor-infiltrating lymphocyte Pembrolizumab Progression-free survival Quality of life Adverse events | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Hussein TA, H. Flaih M. Comparing the Efficacy and Safety of Tumor-Infiltrating Lymphocyte Therapy and Pembrolizumab in Advanced Melanoma: A Randomized Controlled Trial. Acta Med Iran. 2025;63(6):376-385.
