Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma

Nature Reviews Clinical Oncology volume 21, pages 173–184 (2024)Cite this article

Subjects

Abstract

Immunotherapy with immune-checkpoint inhibitors (ICIs) and targeted therapy with BRAF and MEK inhibitors have revolutionized the treatment of melanoma over the past decade. Despite these breakthroughs, the 5-year survival rate of patients with advanced-stage melanoma is at most 50%, emphasizing the need for additional therapeutic strategies. Adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) is a therapeutic modality that has, in the past few years, demonstrated long-term clinical benefit in phase II/III trials involving patients with advanced-stage melanoma, including those with disease progression on ICIs and/or BRAF/MEK inhibitors. In this Review, we summarize the current status of TIL therapies for patients with advanced-stage melanoma, including potential upcoming marketing authorization, the characteristics of TIL therapy products, as well as future strategies that are expected to increase the efficacy of this promising cellular immunotherapy.

Key points

  • Tumour-infiltrating lymphocyte (TIL) therapy shows consistent clinical activity in patients with advanced-stage melanoma, including after disease progression on or after immune-checkpoint inhibitors and BRAF plus MEK inhibitors, and is manageable in most patients.

  • Selection of tumour-reactive T cells and improvements in T cell function during the manufacturing process are expected to further improve the clinical activity of TIL therapy while limiting toxicity.

  • Further clinical implementation of TIL therapy will require the establishment of infrastructure for centralized TIL production or point-of-care manufacturing, as well as treatment by an experienced medical team.

  • Centralized TIL production and treatment of patients at dedicated centres might be important to enhance the clinical feasibility of TIL therapy and will drive further technological innovation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: From a metastatic lesion to a multireactive tumour-infiltrating lymphocyte product.
Fig. 2: Typical timeline for manufacturing and administration of tumour-infiltrating lymphocyte therapy.
Fig. 3: Potential strategies to improve the safety and/or activity of tumour-infiltrating lymphocyte therapy.

Similar content being viewed by others

References

  1. Curti, B. D. & Faries, M. B. Recent advances in the treatment of melanoma. N. Engl. J. Med. 384, 2229–2240 (2021).

    Article  CAS  PubMed  Google Scholar 

  2. Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Marofi, F. et al. CAR T cells in solid tumors: challenges and opportunities. Stem Cell Res. Ther. 12, 81 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011). An important early study showing the durability of response after TIL therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ilyas, S. & Yang, J. C. Landscape of tumor antigens in T cell immunotherapy. J. Immunol. 195, 5117–5122 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Huuhtanen, J. et al. Evolution and modulation of antigen-specific T cell responses in melanoma patients. Nat. Commun. 13, 5988 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Clark, W. H. Jr et al. Model predicting survival in stage I melanoma based on tumor progression. J. Natl Cancer Inst. 81, 1893–1904 (1989).

    Article  PubMed  Google Scholar 

  8. Elder, D. E. et al. The role of lymph node dissection for clinical stage I malignant melanoma of intermediate thickness (1.51-3.99 mm). Cancer 56, 413–418 (1985).

    Article  CAS  PubMed  Google Scholar 

  9. Saldanha, G., Flatman, K., Teo, K. W. & Bamford, M. A novel numerical scoring system for melanoma tumor-infiltrating lymphocytes has better prognostic value than standard scoring. Am. J. Surg. Pathol. 41, 906–914 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Azimi, F. et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J. Clin. Oncol. 30, 2678–2683 (2012).

    Article  PubMed  Google Scholar 

  11. Verdegaal, E. M. et al. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 536, 91–95 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Wong, P. F. et al. Multiplex quantitative analysis of tumor-infiltrating lymphocytes and immunotherapy outcome in metastatic melanoma. Clin. Cancer Res. 25, 2442–2449 (2019).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Scheper, W. et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat. Med. 25, 89–94 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Hudson, W. H. & Wieland, A. Technology meets TILs: deciphering T cell function in the omics era. Cancer Cell 41, 41–57 (2023).

    Article  CAS  PubMed  Google Scholar 

  16. Oliveira, G. et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature 596, 119–125 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bai, X. & Quek, C. Unravelling tumour microenvironment in melanoma at single-cell level and challenges to checkpoint immunotherapy.Genes 13, 1757 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).

    Article  PubMed  Google Scholar 

  19. Lowery, F. J. et al. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers. Science 375, 877–884 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Simoni, Y. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018). This study provides important insights into the composition and reactivity of TILs in human cancers.

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Thommen, D. S. et al. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24, 994–1004 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sarnaik, A. A. et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J. Clin. Oncol. 39, 2656–2666 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rohaan, M. W. et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N. Engl. J. Med. 387, 2113–2125 (2022). The first randomized phase III trial, to our knowledge, providing comparative data on the efficacy of TILs with important implications for the current treatment landscape of melanoma.

    Article  CAS  PubMed  Google Scholar 

  24. Shain, A. H. et al. The genetic evolution of melanoma from precursor lesions. N. Engl. J. Med. 373, 1926–1936 (2015).

    Article  PubMed  Google Scholar 

  25. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016). This study underlines the importance of targeting neoantigens.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. McGranahan, N. & Swanton, C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168, 613–628 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Poschke, I. C. et al. The outcome of ex vivo TIL expansion is highly influenced by spatial heterogeneity of the tumor T-cell repertoire and differences in intrinsic in vitro growth capacity between T-cell clones. Clin. Cancer Res. 26, 4289–4301 (2020).

    Article  CAS  PubMed  Google Scholar 

  28. Gattinoni, L. et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202, 907–912 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Anthony, S. M. et al. Inflammatory signals regulate IL-15 in response to lymphodepletion. J. Immunol. 196, 4544–4552 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Nissani, A. et al. Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy. J. Immunother. Cancer 9, e001743 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Rosen, D.B. et al. TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer. J. Immunother. Cancer 10, e004991 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mo, F. et al. An engineered IL-2 partial agonist promotes CD8+ T cell stemness. Nature 597, 544–548 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. Goff, S. L. et al. Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL. J. Immunother. 33, 840–847 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Dafni, U. et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Ann. Oncol. 30, 1902–1913 (2019). A systematic review and meta-analysis of the outcomes of 410 patients with metastatic melanoma receiving TIL therapy, highlighting similar response rates across multiple studies and patient populations.

    Article  CAS  PubMed  Google Scholar 

  35. Chesney, J. et al. 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.J. Immunother. Cancer 10, e005755 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Goff, S. L. et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J. Clin. Oncol. 34, 2389–2397 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zippel, D. et al. Tissue harvesting for adoptive tumor infiltrating lymphocyte therapy in metastatic melanoma. Anticancer Res. 39, 4995–5001 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Ben-Avi, R. et al. Metastatic lung lesions as a preferred resection site for immunotherapy with tumor infiltrating lymphocytes. J. Immunother. 39, 218–222 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Rohaan, M. et al. Location and size of metastasectomy in melanoma patients treated with tumor-infiltrating lymphocytes (TIL) in relation to clinical outcome. Immuno Oncol. Technol. https://doi.org/10.1016/j.iotech.2022.100141 (2022).

    Article  Google Scholar 

  40. Radvanyi, L. G. et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin. Cancer Res. 18, 6758–6770 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Harel, M. et al. Proteomics of melanoma response to immunotherapy reveals mitochondrial dependence. Cell 179, 236–250.e18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Krishna, S. et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science 370, 1328–1334 (2020). This study identifies the phenotypic T cell characteristics associated with a response to TILs in patients with advanced-stage melanoma.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dudley, M. E. et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J. Immunother. 24, 363–373 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bright, R., Coventry, B. J., Eardley-Harris, N. & Briggs, N. Clinical response rates from interleukin-2 therapy for metastatic melanoma over 30 years’ experience: a meta-analysis of 3312 patients. J. Immunother. 40, 21–30 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Liu, Y. et al. IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor. Nat. Immunol. 22, 358–369 (2021).

    Article  CAS  PubMed  Google Scholar 

  47. Besser, M. J. et al. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin. Cancer Res. 19, 4792–4800 (2013).

    Article  ADS  CAS  PubMed  Google Scholar 

  48. Seitter, S. J. et al. Impact of prior treatment on the efficacy of adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma. Clin. Cancer Res. 27, 5289–5298 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. O’Malley, D. et al. 492 phase 2 efficacy and safety of autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced cancers. J. Immunother. Cancer 9, A523–A524 (2021).

    Article  Google Scholar 

  50. Mehta, G. U. et al. Outcomes of adoptive cell transfer with tumor-infiltrating lymphocytes for metastatic melanoma patients with and without brain metastases. J. Immunother. 41, 241–247 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Monberg, T. J., Borch, T. H., Svane, I. M. & Donia, M. TIL therapy: facts and hopes. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-22-2428 (2023).

    Article  PubMed  Google Scholar 

  52. Creelan, B. C. et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat. Med. 27, 1410–1418 (2021). This phase I study provides promising results on the effectiveness of TIL therapy in patients with NSCLC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, S. et al. Bystander CD4+ T cells infiltrate human tumors and are phenotypically distinct. Oncoimmunology 11, 2012961 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  ADS  CAS  PubMed  Google Scholar 

  55. Leidner, R. et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N. Engl. J. Med. 386, 2112–2119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kristensen, N.P. et al. Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma. J. Clin. Invest. 132, e150535 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Robertson, J., Salm, M. & Dangl, M. Adoptive cell therapy with tumour-infiltrating lymphocytes: the emerging importance of clonal neoantigen targets for next-generation products in non-small cell lung cancer. Immunooncol. Technol. 3, 1–7 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Fernandez-Poma, S. M. et al. Expansion of tumor-infiltrating CD8+ T cells expressing PD-1 improves the efficacy of adoptive T-cell therapy. Cancer Res. 77, 3672–3684 (2017).

    Article  CAS  PubMed  Google Scholar 

  59. Chatani, P. D. et al. Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests. J. Immunother. Cancer 11, e006264 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  60. van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat. Rev. Cancer 20, 218–232 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hashimoto, K. CD137 as an attractive T cell co-stimulatory target in the TNFRSF for immuno-oncology drug development. Cancers 13, 2288 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Seliktar-Ofir, S. et al. Selection of shared and neoantigen-reactive T cells for adoptive cell therapy based on CD137 separation. Front. Immunol. 8, 1211 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Chacon, J. A. et al. Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8+ melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy. PLoS ONE 8, e60031 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chacon, J. A. et al. Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. Clin. Cancer Res. 21, 611–621 (2015).

    Article  ADS  PubMed  Google Scholar 

  65. Cattaneo, C. M. et al. Identification of patient-specific CD4+ and CD8+ T cell neoantigens through HLA-unbiased genetic screens. Nat. Biotechnol. 41, 783–787 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Foy, S. P. et al. Non-viral precision T cell receptor replacement for personalized cell therapy. Nature 615, 687–696 (2023).

    Article  ADS  CAS  PubMed  Google Scholar 

  67. Janelle, V. & Deslisle, J. S. T-cell dysfunction as a limitation of adoptive immunotherapy: current concepts and mitigation strategies. Cancers 13, 598 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Reina-Campos, M., Scharping, N. E. & Goldrath, A. W. CD8+ T cell metabolism in infection and cancer. Nat. Rev. Immunol. 21, 718–738 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Crompton, J. G. et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 75, 296–305 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Feng, H. et al. Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy. Cancer Med. 12, 3313–3327 (2023).

    Article  CAS  PubMed  Google Scholar 

  71. Thomas, S. & Abken, H. CAR T cell therapy becomes CHIC: “cytokine help intensified CAR” T cells. Front. Immunol. 13, 1090959 (2022).

    Article  CAS  PubMed  Google Scholar 

  72. Narayan, V. et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. 28, 724–734 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kerkar, S. P. et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J. Clin. Invest. 121, 4746–4757 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Leonard, J. P. et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-γ production. Blood 90, 2541–2548 (1997).

    CAS  PubMed  Google Scholar 

  75. Zhang, L. et al. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol. Ther. 19, 751–759 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhang, L. et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21, 2278–2288 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  77. Allen, G. M. et al. Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science 378, eaba1624 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167, 419–432.e16 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Beane, J. D. et al. Clinical scale zinc finger nuclease-mediated gene editing of PD-1 in tumor infiltrating lymphocytes for the treatment of metastatic melanoma. Mol. Ther. 23, 1380–1390 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chamberlain, C. A. et al. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy. Mol. Ther. Oncolytics 24, 417–428 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Palmer, D. C. et al. Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade. Med 3, 682–704.e8 (2022).

    Article  CAS  PubMed  Google Scholar 

  82. Heemskerk, B. et al. Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum. Gene Ther. 19, 496–510 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Corria-Osorio, J. et al. Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells. Nat. Immunol. 24, 869–883 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Passaro, C. et al. Enhancers of innate and adaptive immunity combine with membrane bound IL15 to increase the efficacy of tumor infiltrating lymphocyte (TIL) therapy for tumors with immunosuppressive microenvironments. J. Immunother. Cancer https://doi.org/10.1136/jitc-2022-sitc2022.0369 (2022).

  85. Kazemi, M. H. et al. Tumor-infiltrating lymphocytes for treatment of solid tumors: it takes two to tango? Front. Immunol. 13, 1018962 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chandran, S. S. et al. Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study. Lancet Oncol. 18, 792–802 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Stevanovic, S. et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J. Clin. Oncol. 33, 1543–1550 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Stevanovic, S. et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356, 200–205 (2017).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Aoki, Y. et al. Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer. Cancer Res. 51, 1934–1939 (1991).

    CAS  PubMed  Google Scholar 

  91. Zhen, Y. H. et al. Phase I/II study of adjuvant immunotherapy with sentinel lymph node T lymphocytes in patients with colorectal cancer. Cancer Immunol. Immunother. 64, 1083–1093 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Sebastian Klobuch, Tom T. P. Seijkens.

Authors and Affiliations

  1. Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands

    Sebastian Klobuch, Tom T. P. Seijkens & John B. A. G. Haanen

  2. Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam, Netherlands

    Tom T. P. Seijkens

  3. Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands

    Ton N. Schumacher & John B. A. G. Haanen

  4. Department of Hematology, Leiden University Medical Center, Leiden, Netherlands

    Ton N. Schumacher

  5. Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands

    John B. A. G. Haanen

  6. Melanoma Clinic, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    John B. A. G. Haanen

Authors
  1. Sebastian Klobuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tom T. P. Seijkens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ton N. Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John B. A. G. Haanen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.K., T.T.P.S. and J.B.A.G.H. researched data for the manuscript. All authors made a substantial contribution to discussions of content. S.K., T.T.P.S. and J.B.A.G.H. wrote the manuscript and all authors edited and/or reviewed the manuscript before submission.

Corresponding author

Correspondence to John B. A. G. Haanen.

Ethics declarations

Competing interests

S.K. has acted as an adviser of Regeneron. T.N.S. has acted as an adviser of Allogene Therapeutics, Asher Therapeutics, Celsius, Merus, Neogene Therapeutics and Scenic Biotech; is a stockholder in Allogene Therapeutics, Asher Therapeutics, Cell Control, Celsius, Merus and Scenic Biotech; and is a venture partner at Third Rock Ventures. J.B.A.G.H. has acted as an adviser of Achilles Therapeutics, BioNTech, Bristol Myers Squibb, CureVac, Gadeta, Immunocore, Instil Bio, Iovance Bio, Ipsen, Merck Serono, Molecular Partners, MSD, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Scenic, Seattle Genetics, Third Rock Ventures and T-Knife, and has received research grants from Amgen, Asher Bio, BioNTech, Bristol Myers Squibb, MSD, Novartis and Sastra Cell Therapy. T.T.P.S. declares no competing interests.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks M. Besser and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Klobuch, S., Seijkens, T.T.P., Schumacher, T.N. et al. Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma. Nat Rev Clin Oncol 21, 173–184 (2024). https://doi.org/10.1038/s41571-023-00848-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-023-00848-w

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing