New and emerging therapies in cutaneous T-cell lymphoma
Accepted: 5 August 2024
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Mycosis Fungoides (MF) is the most common cutaneous T-cell lymphoma that typically presents in the early phase as inflammatory erythematous patches or plaques, with epidermotropism as the histopathological hallmark of the disease. Traditionally, in the early stages, non-aggressive options represent the first-line strategy: topical corticosteroids, phototherapy, radiotherapy and occasionally adopting a 'wait-and-see' approach for minimally symptomatic patients. In patients with advanced or recurrence disease, good results can be achieved with immune modifiers, chemotherapeutic agents, total skin irradiation or extracorporeal photochemotherapy and maintenance therapy is often required. The past decade has seen an expansion of therapies that can be used in this setting by increasing new therapeutic strategies. Herein are resumed the key advancements coming from recently published trials.
Latzka J, Assaf C, Bagot M, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023. Eur J Cancer 2023;195:113343.
Durán N, Song PS. Hypericin and its photodynamic action. Photochem Photobiol 1986;43:677-80. DOI: https://doi.org/10.1111/j.1751-1097.1986.tb05646.x
Blank M, Lavie G, Mandel M, et al. Antimetastatic activity of the photodynamic agent hypericin in the dark. Int J Cancer 2004;111:596-603. DOI: https://doi.org/10.1002/ijc.20285
Kamuhabwa AA, Cosserat-Gerardin I, Didelon J, et al. Biodistribution of hypericin in orthotopic transitional cell carcinoma bladder tumors: implication for whole bladder wall photodynamic therapy. Int J Cancer 2002;97:253-60. DOI: https://doi.org/10.1002/ijc.1594
Vandenbogaerde AL, Cuveele JF, Proot P, et al. Differential cytotoxic effects induced after photosensitization by hypericin. J Photochem Photobiol B 1997;38:136-42. DOI: https://doi.org/10.1016/S1011-1344(96)07446-5
Garg AD, Agostinis P. ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses. Photochem Photobiol Sci 2014;13:474-87. DOI: https://doi.org/10.1039/c3pp50333j
Kim EJ, Mangold AR, DeSimone JA, et al. Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial. JAMA Dermatol 2022;158:1031-9. DOI: https://doi.org/10.1001/jamadermatol.2022.2749
Choi J, Goh G, Walradt T, et al. Genomic landscape of cutaneous T cell lymphoma. Nat Genet 2015;47:1011-9. DOI: https://doi.org/10.1038/ng.3356
Vaqué JP, Gómez-López G, Monsálvez V, et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood 2014;123:2034-43. DOI: https://doi.org/10.1182/blood-2013-05-504308
Ortiz-Romero PL, Maroñas Jiménez L, Muniesa C, et al. Activity and safety of topical pimecrolimus in patients with early stage mycosis fungoides (PimTo-MF): a single-arm, multicentre, phase 2 trial. Lancet Haematol 2022;9:e425-33. DOI: https://doi.org/10.1016/S2352-3026(22)00107-7
Battistella M, Leboeuf C, Ram-Wolff C, et al. KIR3DL2 expression in cutaneous T-cell lymphomas: expanding the spectrum for KIR3DL2 targeting. Blood 2017;130:2900-2. DOI: https://doi.org/10.1182/blood-2017-06-792382
Marie-Cardine A, Viaud N, Thonnart N, et al. IPH4102, a humanized KIR3DL2 antibody with potent activity against cutaneous T-cell lymphoma. Cancer Res 2014;74:6060-70. DOI: https://doi.org/10.1158/0008-5472.CAN-14-1456
Bagot M, Porcu P, Marie-Cardine A, et al. IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial. Lancet Oncol 2019;20:1160-70. DOI: https://doi.org/10.1016/S1470-2045(19)30320-1
Lai P, Wang Y. Epigenetics of cutaneous T-cell lymphoma: biomarkers and therapeutic potentials. Cancer Biol Med 2021;18:34-51. DOI: https://doi.org/10.20892/j.issn.2095-3941.2020.0216
Foss F, Advani R, Duvic M, et al. A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol 2015;168:811-9. DOI: https://doi.org/10.1111/bjh.13222
Stadler R, Scarisbrick JJ. Maintenance therapy in patients with mycosis fungoides or Sézary syndrome: A neglected topic. Eur J Cancer 2021;142:38-47. DOI: https://doi.org/10.1016/j.ejca.2020.10.007
Chong BF, Wilson AJ, Gibson HM, et al. Immune function abnormalities in peripheral blood mononuclear cell cytokine expression differentiates stages of cutaneous T-cell lymphoma/mycosis fungoides. Clin Cancer Res 2008;14:646-53. DOI: https://doi.org/10.1158/1078-0432.CCR-07-0610
Shalabi D, Bistline A, Alpdogan O, et al. Immune evasion and current immunotherapy strategies in mycosis fungoides (MF) and Sézary syndrome (SS). Chin Clin Oncol 2019;8:11. DOI: https://doi.org/10.21037/cco.2019.01.01
Vowels BR, Lessin SR, Cassin M, et al. Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma. J Invest Dermatol 1994;103:669-73. DOI: https://doi.org/10.1111/1523-1747.ep12398454
Zarour HM. Reversing T-cell dysfunction and exhaustion in cancer. Clin Cancer Res 2016;22:1856-64. DOI: https://doi.org/10.1158/1078-0432.CCR-15-1849
Kantekure K, Yang Y, Raghunath P, et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. Am J Dermatopathol 2012;34:126-8. DOI: https://doi.org/10.1097/DAD.0b013e31821c35cb
Roccuzzo G, Giordano S, Fava P, et al. Immune check point inhibitors in primary cutaneous t-cell lymphomas: biologic rationale, clinical results and future perspectives. Front Oncol 2021;11:733770. DOI: https://doi.org/10.3389/fonc.2021.733770
Samimi S, Benoit B, Evans K, et al. Increased programmed death-1 expression on CD4+ T cells in cutaneous T-cell lymphoma: implications for immune suppression. Arch Dermatol 2010;146:1382-8. DOI: https://doi.org/10.1001/archdermatol.2010.200
Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol 2011;350:17-37. DOI: https://doi.org/10.1007/82_2010_116
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med 2016;8:328rv4. DOI: https://doi.org/10.1126/scitranslmed.aad7118
Schietinger A, Greenberg PD. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol 2014;35:51-60. DOI: https://doi.org/10.1016/j.it.2013.10.001
Quaglino P, Fava P, Pileri A, et al. Phenotypical Markers, Molecular Mutations, and Immune Microenvironment as Targets for New Treatments in Patients with Mycosis Fungoides and/or Sézary Syndrome. J Invest Dermatol 2021;141:484-95. DOI: https://doi.org/10.1016/j.jid.2020.07.026
Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol 2016;34:2698-704. DOI: https://doi.org/10.1200/JCO.2015.65.9789
Khodadoust MS, Rook AH, Porcu P, et al. Pembrolizumab in relapsed and refractory mycosis fungoides and sézary syndrome: a multicenter phase II study. J Clin Oncol 2020;38:20-8. DOI: https://doi.org/10.1200/JCO.19.01056
Marchi E, Ma H, Montanari F, et al. The Integration of PD1 Blockade With Epigenetic Therapy is Highly Active and Safe in Heavily Treated Patients With T-Cell Lymphoma (PTCL) and Cutaneous T-Cell Lymphoma (CTCL). J Clin Oncol 2020;38:8049. DOI: https://doi.org/10.1200/JCO.2020.38.15_suppl.8049
Bar-Sela G, Bergman R. Complete regression of mycosis fungoides after ipilimumab therapy for advanced melanoma. JAAD Case Rep 2015;1:99-100. DOI: https://doi.org/10.1016/j.jdcr.2015.02.009
Sekulic A, Liang WS, Tembe W, et al. Personalized treatment of Sézary syndrome by targeting a novel CTLA4:CD28 fusion. Mol Genet Genomic Med 2015;3:130-6. DOI: https://doi.org/10.1002/mgg3.121
Latzka J, Assaf C, Bagot M, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023. Eur J Cancer 2023;195:113343. DOI: https://doi.org/10.1016/j.ejca.2023.113343
Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138:286-99. DOI: https://doi.org/10.1016/j.cell.2009.05.045
Liu X, Pu Y, Cron K, et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med 2015;21:1209-15. DOI: https://doi.org/10.1038/nm.3931
Ring NG, Herndler-Brandstetter D, Weiskopf K, et al. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc Nat Acad Sci United States Am 2017;114:E10578-85. DOI: https://doi.org/10.1073/pnas.1710877114
Weiskopf K, Jahchan NS, Schnorr PJ, et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest 2016;126:2610-20. DOI: https://doi.org/10.1172/JCI81603
Querfeld C, Thompson JA, Taylor MH, et al. Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study. Lancet Haematol 2021;8:e808-17. DOI: https://doi.org/10.1016/S2352-3026(21)00271-4
ClinicalTrials.gov Identifier: NCT04541017
ClinicalTrials.gov Identifier: NCT02953509
Bullock TN, Yagita H. Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ T cell responses in the absence of CD4+ T cells. J Immunol 2005;174:710-7. DOI: https://doi.org/10.4049/jimmunol.174.2.710
Lens SM, Baars PA, Hooibrink B, et al. Antigen-presenting cell-derived signals determine expression levels of CD70 on primed T cells. Immunology 1997;90:38-45. DOI: https://doi.org/10.1046/j.1365-2567.1997.00134.x
Wu CH, Wang L, Yang CY, et al. Targeting CD70 in cutaneous T-cell lymphoma using an antibody-drug conjugate in patient-derived xenograft models. Blood Adv 2022;6:2290-302. DOI: https://doi.org/10.1182/bloodadvances.2021005714
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