Application and Advances of Adoptive Cell Therapy for Melanoma

Abstract

Melanoma is a highly aggressive malignancy originating from melanocytes. Patients with advanced melanoma have a poor prognosis, with a high risk of distant metastasis and resistance to targeted therapy or immunotherapy. In recent years, adoptive cell therapy (ACT), an emerging personalized immunotherapy, has made significant progress in the treatment and investigation of melanoma. This review provides a comprehensive overview of ACT in melanoma, emphasizing its current application, therapeutic benefits, prevailing challenges, and future prospects, with particular focus on four major strategies: tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor T cells (CAR-T), T cell receptor-engineered T cells (TCR-T), and other immune cell-based therapies. With continuous evolution of bioengineering and precision medicine, ACT holds increasing potential for treating melanoma and other solid tumors, offering new avenues for clinical translation.

Keywords

Melanoma / Adoptive cell therapy

References

[1] LongGV, SwetterSM, MenziesAM, GershenwaldJE, ScolyerRA. Cutaneous melanoma. Lancet, 2023, 402(10400): 485-502

[2] RussoAE, TorrisiE, BevelacquaY, et al.. Melanoma: molecular pathogenesis and emerging target therapies (Review). Int J Oncol, 2009, 34(6): 1481-1489

[3] FriedmanEB, ShangS, de MieraEV, et al.. Serum microRNAs as biomarkers for recurrence in melanoma. J Transl Med, 2012, 10155

[4] SchadendorfD, van AkkooiACJ, BerkingC, et al.. Melanoma. Lancet, 2018, 392(10151): 971-84

[5] RobertC, CarlinoMS, McNeilC, et al.. Seven-year follow-up of the phase III KEYNOTE-006 study: pembrolizumab versus ipilimumab in advanced melanoma. J Clin Oncol, 2023, 41(24): 3998-4003

[6] ChesneyJ, LewisKD, KlugerH, 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, 2022.

[7] AntonyPA, PiccirilloCA, AkpinarliA, et al.. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol, 2005, 174(5): 2591-601

[8] AtkinsMB, LotzeMT, DutcherJP, et al.. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol, 1999, 17(7): 2105-2116

[9] RosenbergSA, LotzeMT, MuulLM, et al.. A new approach to the therapy of cancer based on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2. Surgery, 1986, 100(2): 262-272

[10] DafniU, MichielinO, LluesmaSM, 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, 2019, 30(12): 1902-13

[11] van den BergJH, HeemskerkB, van RooijN, et al.. Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up. J Immunother Cancer, 2020.

[12] RohaanMW, BorchTH, van den BergJH, et al.. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N Engl J Med, 2022, 387(23): 2113-2125

[13] ChandranSS, SomervilleRPT, YangJC, 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, 2017, 18(6): 792-802

[14] VeatchJR, SimonS, RiddellSR. Tumor-infiltrating lymphocytes make inroads in non-small-cell lung cancer. Nat Med, 2021, 27(8): 1339-1341

[15] HuangH, NieC, LiuX, et al.. Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer. J Clin Invest, 2022.

[16] RosenbergSA, YangJC, SherryRM, et al.. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res, 2011, 17(13): 4550-7

[17] DumauthiozN, TschumiB, WenesM, et al.. Enforced PGC-1alpha expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell Mol Immunol, 2021, 18(7): 1761-1771

[18] FeinsS, KongW, WilliamsEF, MiloneMC, FraiettaJA. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol, 2019, 94(S1): S3-9

[19] RoselliE, BoucherJC, LiG, et al.. 4–1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells. J Immunother Cancer, 2021.

[20] ChmielewskiM, HombachAA, AbkenH. Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev, 2014, 257(1): 83-90

[21] DimitriA, HerbstF, FraiettaJA. Engineering the next-generation of CAR T-cells with CRISPR-Cas9 gene editing. Mol Cancer, 2022, 21178

[22] PorterDL, LevineBL, KalosM, BaggA, JuneCH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med, 2011, 365(8): 725-733

[23] MaudeSL, LaetschTW, BuechnerJ, et al.. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med, 2018, 378(5): 439-448

[24] MishraAK, KemlerI, DingliD. Preclinical development of CD126 CAR-T cells with broad antitumor activity. Blood Cancer J, 2021, 1113

[25] ChinnasamyD, YuZ, TheoretMR, et al.. Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. J Clin Invest, 2010, 120(11): 3953-68

[26] YangM, TangX, ZhangZ, et al.. Tandem CAR-T cells targeting CD70 and B7–H3 exhibit potent preclinical activity against multiple solid tumors. Theranostics, 2020, 10(17): 7622-7634

[27] SoltantoyehT, AkbariB, KarimiA, et al.. Chimeric antigen receptor (CAR) T cell therapy for metastatic melanoma: challenges and road ahead. Cells, 2021.

[28] YuJ, WuX, YanJ, et al.. Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients. J Hematol Oncol, 2018, 1111

[29] KaczanowskaS, MurtyT, AlimadadiA, et al.. Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer Cell, 2024, 42(1): 35-51.e8

[30] FischerGM, Vashisht GopalYN, McQuadeJL, et al.. Metabolic strategies of melanoma cells: mechanisms, interactions with the tumor microenvironment, and therapeutic implications. Pigment Cell Melanoma Res, 2018, 31(1): 11-30

[31] ShaferP, KellyLM, HoyosV. Cancer therapy with TCR-engineered T cells: current strategies, challenges, and prospects. Front Immunol, 2022, 13835762

[32] KawakamiY, EliyahuS, DelgadoCH, et al.. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci U S A, 1994, 91(9): 3515-9

[33] BakkerAB, SchreursMW, de BoerAJ, et al.. Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes. J Exp Med, 1994, 179(3): 1005-9

[34] MorganRA, DudleyME, WunderlichJR, et al.. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, 2006, 314(5796): 126-129

[35] JohnsonLA, MorganRA, DudleyME, et al.. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood, 2009, 114(3): 535-546

[36] RobbinsPF, MorganRA, FeldmanSA, et al.. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol, 2011, 29(7): 917-24

[37] NagarshethNB, NorbergSM, SinkoeAL, et al.. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med, 2021, 27(3): 419-425

[38] WronaE, BorowiecM, PotemskiP. CAR-NK cells in the treatment of solid tumors. Int J Mol Sci, 2021.

[39] LiuE, MarinD, BanerjeeP, et al.. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med, 2020, 382(6): 545-553

[40] PoonAYC, SugimuraR. The prospect of genetically engineering natural killer cells for cancer immunotherapy. Biol Open, 2022.

[41] KlobuchS, SeijkensTTP, SchumacherTN, HaanenJBAG. Tumour-infiltrating lymphocyte therapy for patients with advanced-stage melanoma. Nat Rev Clin Oncol, 2024, 21(3): 173-184

[42] SchumacherTN, SchreiberRD. Neoantigens in cancer immunotherapy. Science, 2015, 348(6230): 69-74

[43] KristensenNP, HeekeC, TvingsholmSA, et al.. Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma. J Clin Invest, 2022.

[44] Fernandez-PomaSM, Salas-BenitoD, LozanoT, et al.. Expansion of tumor-infiltrating CD8(+) T cells expressing PD-1 improves the efficacy of adoptive T-cell therapy. Cancer Res, 2017, 77(13): 3672-84

[45] ChataniPD, LoweryFJ, ParikhNB, et al.. Cell surface marker-based capture of neoantigen-reactive CD8(+) T-cell receptors from metastatic tumor digests. J Immunother Cancer, 2023.

[46] van der LeunAM, ThommenDS, SchumacherTN. CD8(+) T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer, 2020, 20(4): 218-32

[47] HashimotoK. CD137 as an attractive T cell co-stimulatory target in the TNFRSF for immuno-oncology drug development. Cancers (Basel), 2021.

[48] Seliktar-OfirS, Merhavi-ShohamE, ItzhakiO, et al.. Selection of shared and neoantigen-reactive T cells for adoptive cell therapy based on CD137 separation. Front Immunol, 2017, 81211

[49] ChaconJA, WuRC, SukhumalchandraP, 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, 2013, 84e60031

[50] ChaconJA, SarnaikAA, ChenJQ, et al.. Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. Clin Cancer Res, 2015, 21(3): 611-21

[51] YangM, TangX, ZhangZ, et al.. Tandem CAR-T cells targeting CD70 and B7–H3 exhibit potent preclinical activity against multiple solid tumors. Theranostics, 2020, 10(17): 7622-7634

[52] ChenN, PuC, ZhaoL, et al.. 644 A phase 1 dose escalation study of GCC19CART – A novel CoupledCAR® therapy for subjects with metastatic colorectal cancer. J Immunother Cancer, 2023, 11Suppl 1737

[53] HeW, CuiK, FarooqMA, et al.. TCR-T cell therapy for solid tumors: challenges and emerging solutions. Front Pharmacol, 2025, 161493346

[54] Bispecific chimeric T cell receptors tackle tumor heterogeneity. Nat Cancer. 2025;6(4):571–2

[55] WangX, DaiZ, LinX, et al.. Antigen/HLA-agnostic strategies for characterizing tumor-responsive T cell receptors in PDAC patients via single-cell sequencing and autologous organoid application. Cancer Lett, 2024, 588216741

[56] YangQ, NaJ, QinS, et al.. Anticancer mechanisms and applications based on γδ T cells in cancer immunotherapy. Crit Rev Oncol Hematol, 2025, 214104814

[57] Janelle V, Delisle J. T-cell dysfunction as a limitation of adoptive immunotherapy: current concepts and mitigation strategies. Cancers (Basel). 2021;13(4):598.

[58] CromptonJG, SukumarM, RoychoudhuriR, et al.. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res, 2015, 75(2): 296-305

[59] KrishnaS, LoweryFJ, CopelandAR, et al.. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science, 2020, 370(6522): 1328-1334

[60] FengH, QiuL, ShiZ, et al.. Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy. Cancer Med, 2023, 12(3): 3313-27

[61] ZhangL, KerkarSP, YuZ, et al.. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol Ther, 2011, 19(4): 751-9

[62] ZhangL, MorganRA, BeaneJD, et al.. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res, 2015, 21(10): 2278-88

[63] BeaneJD, LeeG, ZhengZ, 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, 2015, 23(8): 1380-90

[64] ChamberlainCA, BennettEP, KvernelandAH, et al.. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy. Mol Ther, 2022, 24: 417-28

[65] PalmerDC, WebberBR, PatelY, et al.. Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade. Med (N Y), 2022, 3(10): 682-704.e8

[66] CuiG, StaronMM, GraySM, et al.. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity. Cell, 2015, 161(4): 750-761

[67] ZhangZ, JiangC, LiuZ, et al.. B7-H3-targeted CAR-T cells exhibit potent antitumor effects on hematologic and solid tumors. Mol Ther, 2020, 17: 180-189

[68] KershawMH, WangG, WestwoodJA, et al.. Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum Gene Ther, 2002, 13(16): 1971-80

[69] CaruanaI, SavoldoB, HoyosV, et al.. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med, 2015, 21(5): 524-529

[70] SoltantoyehT, AkbariB, KarimiA, et al.. Chimeric antigen receptor (CAR) T cell therapy for metastatic melanoma: challenges and road ahead. Cells, 2021.

[71] Guha P, Heatherton KR, O'Connell KP, Alexander IS, Katz SC. Assessing the Future of Solid Tumor Immunotherapy. Biomedicines. 2022;10(3):655.

[72] ArnerEN, RathmellJC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell, 2023, 41(3): 421-433

[73] BerraondoP, SanmamedMF, OchoaMC, et al.. Cytokines in clinical cancer immunotherapy. Br J Cancer, 2019, 120(1): 6-15

[74] LinH, LiuC, HuA, et al.. Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives. J Hematol Oncol, 2024, 17131

[75] XiaC, YinS, ToKKW, FuL. CD39/CD73/A2AR pathway and cancer immunotherapy. Mol Cancer, 2023, 22144

[76] Abdoli ShadbadM, HemmatN, Khaze ShahgoliV, et al.. A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to Personalized Medicine. Front Immunol, 2021, 12788211

[77] ChangY, ChangM, BaoX, DongC. Advancements in adoptive CAR immune cell immunotherapy synergistically combined with multimodal approaches for tumor treatment. Bioact Mater, 2024, 42: 379-403

[78] BertrandF, MontfortA, MarcheteauE, et al.. TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma. Nat Commun, 2017, 812256

[79] TangN, ChengC, ZhangX, et al.. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight, 2020.

[80] ChmielewskiM, KopeckyC, HombachAA, AbkenH. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res, 2011, 71(17): 5697-706

[81] HuB, RenJ, LuoY, et al.. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep, 2017, 20(13): 3025-33

[82] NissaniA, Lev-AriS, MeirsonT, et al.. Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy. J Immunother Cancer, 2021.

[83] HeemskerkB, LiuK, DudleyME, et al.. Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum Gene Ther, 2008, 19(5): 496-510

[84] Corria-OsorioJ, CarmonaSJ, StefanidisE, et al.. Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8(+) T cells. Nat Immunol, 2023, 24(5): 869-83

[85] PassaroC, KoscsoB, SmithS, et al.. 369 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, 2022, 10Suppl 2A388

[86] FedorovVD, ThemeliM, SadelainM. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med, 2013, 5215215ra172

[87] LanitisE, PoussinM, KlattenhoffAW, et al.. Chimeric antigen receptor T cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol Res, 2013, 1(1): 43-53

[88] Di StasiA, TeyS, DottiG, et al.. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med, 2011, 365(18): 1673-1683

[89] EvginL, KottkeT, TonneJ, et al.. Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice. Sci Transl Med, 2022, 14640eabn2231

[90] ChenQ, HuQ, DukhovlinovaE, et al.. Photothermal Therapy Promotes Tumor Infiltration and Antitumor Activity of CAR T Cells. Adv Mater, 2019, 3123e1900192

[91] van den BergJH, HeemskerkB, van RooijN, et al.. Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up. J Immunother Cancer, 2020.

[92] MarotteL, CapitaoM, DeleineC, et al.. Anti-tumor efficacy of a combination therapy with PD-L1 targeted alpha therapy and adoptive cell transfer of PD-1 deficient melanoma-specific human T-lymphocytes. Oncoimmunology, 2021, 1011940676

[93] WachsmannTLA, MeeuwsenMH, RemstDFG, et al.. Combining BCMA-targeting CAR T cells with TCR-engineered T-cell therapy to prevent immune escape of multiple myeloma. Blood Adv, 2023, 7(20): 6178-83

[94] HuangY, QinY, HeY, et al.. Advances in molecular targeted drugs in combination with CAR-T cell therapy for hematologic malignancies. Drug Resist Updat, 2024, 74101082

Funding

National Natural Science Foundation of China(82203528)

Postdoctoral Science Foundation of Jiangsu Province(2022M710769)

RIGHTS & PERMISSIONS

The Author(s)