NIVO-TIL: combination anti-PD-1 therapy and adoptive T-cell transfer in untreated metastatic melanoma: an exploratory open-label phase I trial
DOI:
https://doi.org/10.2340/1651-226X.2024.40495Keywords:
Immunotherapy, Immunotherapy Anti-PD-1, TILs, Adoptive cell transfer, melanomaAbstract
Background and purpose: In patients with metastatic melanoma who respond to anti-PD-1 therapy, the proliferation of intra-tumour CD8+ T cells is directly correlated with the clinical response, making tumour-infiltrating lymphocytes (TILs) a treatment of interest in combination with a PD-1 inhibitor, which is the undisputed gold standard in the management of metastatic melanoma. The aim of this trial was, therefore, to evaluate the safety and efficacy of sequential combination therapy consisting of nivolumab (a PD-1 inhibitor) and TILs adoptive T cells in patients with metastatic melanoma.
Materials and methods: We performed an exploratory, prospective, single-centre, open-label, non-randomised, uncontrolled phase I/II study. We enrolled 10 previously untreated patients with advanced melanoma. The treatment regimen was neoadjuvant anti-PD-1 therapy followed by 2 injections of TILs and a second sequence of anti-PD-1 therapy.
Results and interpretation: Among the four patients who received the autologous TILs + nivolumab combination, three (75%) achieved an objective response (two achieved a partial response [PR] at the end of the study, two achieved a complete response [CR]), and one achieved a CR at the end of the study. Among these three patients, one had a PR, and two had stable disease (SD) after the nivolumab course and before any TILs administration, reinforcing the importance of the tumour response after TILs injection. These responses were persistent, ranging from 9 months to 3.4 years.
Downloads
References
Zhao L, Yang Y, Li W, Han L, Lin H, Gao Q. Rapid complete remission of metastatic mela-noma after first-line treatment with nivolumab plus tumor-infiltrating lym-phocytes. Immunotherapy. 2018;10:1133–6.
https://doi.org/10.2217/imt-2018-0056 DOI: https://doi.org/10.2217/imt-2018-0056
Ugurel S, Röhmel J, Ascierto PA, Flaherty KT, Grob JJ, Hauschild A et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. Eur J Cancer. 2017;83:247–57.
https://doi.org/10.1016/j.ejca.2017.06.028 DOI: https://doi.org/10.1016/j.ejca.2017.06.028
Robert C, Long GV, Brady B, Dutriaux C, Di Giacomo AM, Mortier L, et al. Five-year out-comes with nivolumab in patients with wild-type BRAF advanced melanoma. J Clin Oncol. 2020;38:3937–46.
https://doi.org/10.1200/jco.20.00995 DOI: https://doi.org/10.1200/JCO.20.00995
Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019;20:1239–51.
https://doi.org/10.1016/s1470-2045(19)30388-2 DOI: https://doi.org/10.1016/S1470-2045(19)30388-2
Diaz-Cano I, Paz-Ares L, Otano I. Adoptive tumor infiltrating lymphocyte transfer as per-sonalized immunotherapy. Int Rev Cell Mol Biol. 2022;370:163–92.
https://doi.org/10.1016/bs.ircmb.2022.04.003 DOI: https://doi.org/10.1016/bs.ircmb.2022.04.003
Amaria RN, Menzies AM, Burton EM, Scolyer RA, Tetzlaff MT, Antdbacka R, et al. Neoadju-vant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. Lancet Oncol. 2019;20:e378–89.
https://doi.org/10.1016/s1470-2045(19)30332-8 DOI: https://doi.org/10.1016/S1470-2045(19)30332-8
Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immu-notherapy. Science. 2020;367:eaax0182.
https://doi.org/10.1126/science.aax0182 DOI: https://doi.org/10.1126/science.aax0182
Versluis JM, Long GV, Blank CU. Learning from clinical trials of neoadjuvant checkpoint blockade. Nat Med. 2020;26:475–84.
https://doi.org/10.1038/s41591-020-0829-0 DOI: https://doi.org/10.1038/s41591-020-0829-0
Patel SP, Othus M, Chen Y, Wright GP, Yost KJ, Hyngstrom JR, et al. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med. 2023;388:813–23.
https://doi.org/10.1056/NEJMoa2211437 DOI: https://doi.org/10.1056/NEJMoa2211437
Lucas MW, Lijnsvelt J, Pulleman S, Scolyer RA, Menzies AM, Van Akkooi ACJ, et al. The NADINA trial: a multicenter, randomised, phase 3 trial comparing the efficacy of neoadjuvant ipilimumab plus nivolumab with standard adjuvant nivolumab in macroscopic resectable stage III melanoma. J Clin Oncol. 2022;40:TPS9605.
https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS9605 DOI: https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS9605
Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537–44.
https://doi.org/10.1182/blood-2008-12-195792 DOI: https://doi.org/10.1182/blood-2008-12-195792
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.
https://doi.org/10.1038/nature04444 DOI: https://doi.org/10.1038/nature04444
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.
https://doi.org/10.1038/nature13954 DOI: https://doi.org/10.1038/nature13954
Islam SMR, Maeda T, Tamaoki N, Good ML, Kishton RJ, Paria BC, et al. Reprogramming of tumor-reactive tumor-infiltrating lymphocytes to human-induced pluripo-tent stem cells. Cancer Res Commun. 2023;3:917–32.
https://doi.org/10.1158/2767-9764.crc-22-0265 DOI: https://doi.org/10.1158/2767-9764.CRC-22-0265
Rohaan MW, Borch TH, Van den Berg JH, Met Ö, Kessels R, Foppen MHG, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N Engl J Med. 2022;387:2113–25.
https://doi.org/10.1056/NEJMoa2210233 DOI: https://doi.org/10.1056/NEJMoa2210233
Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, et al. Observa-tions on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313:1485–92.
https://doi.org/10.1056/nejm198512053132327 DOI: https://doi.org/10.1056/NEJM198512053132327
Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994;86:1159–66.
https://doi.org/10.1093/jnci/86.15.1159 DOI: https://doi.org/10.1093/jnci/86.15.1159
Marotte L, Capitao M, Deleine C, Beauvais T, Cadiou G, Perrin J, 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. Onco-immunology. 2021;10:1940676.
https://doi.org/10.1080/2162402x.2021.1940676 DOI: https://doi.org/10.1080/2162402X.2021.1940676
Dréno B, Khammari A, Fortun A, Vignard V, Saiagh S, Beauvais T, et al. Phase I/II clinical trial of adoptive cell transfer of sorted specific T cells for metastatic mela-noma patients. Cancer Immunol Immunother. 2021;70:3015–30.
https://doi.org/10.1007/s00262-021-02961-0 DOI: https://doi.org/10.1007/s00262-021-02961-0
Jotereau F, Pandolfino MC, Boudart D, Diez E, Dreno B, Douillard JY, et al. High-fold expan-sion of human cytotoxic T-lymphocytes specific for autologous melanoma cells for use in immunotherapy. J Immunother (1991). 1991;10:405–11.
https://doi.org/10.1097/00002371-199112000-00003 DOI: https://doi.org/10.1097/00002371-199112000-00003
Tessier MH, Pandolfino MC, Jotereau F, Boudart D, Litoux P, Dréno B. Home therapy with autologous tumour-infiltrating lymphocytes and subcutaneous interleukin-2 in metastatic melanoma. Eur J Cancer. 1996;32a:735–6.
https://doi.org/10.1016/0959-8049(95)00651-6 DOI: https://doi.org/10.1016/0959-8049(95)00651-6
Khammari A, Nguyen JM, Leccia MT, Guillot B, Saiagh S, Pandolfino MC, et al. Tumor infil-trating lymphocytes as adjuvant treatment in stage III melanoma patients with only one invaded lymph node after complete resection: results from a multicentre, randomized clinical phase III trial. Cancer Immunol Immunoth-er. 2020;69:1663–1672.
https://doi.org/10.1007/s00262-020-02572-1 DOI: https://doi.org/10.1007/s00262-020-02572-1
Khammari A, Nguyen JM, Pandolfino MC, Quereux G, Brocard A, Bercegeay S, et al. Long-term follow-up of patients treated by adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother. 2007;56:1853–60.
https://doi.org/10.1007/s00262-007-0340-1 DOI: https://doi.org/10.1007/s00262-007-0340-1
Labarrière N, Pandolfino MC, Gervois N, Khammari A, Tessier MH, Dréno B, et al. Thera-peutic efficacy of melanoma-reactive TIL injected in stage III melanoma pa-tients. Cancer Immunol Immunother. 2002;51:532–8.
https://doi.org/10.1007/s00262-002-0313-3 DOI: https://doi.org/10.1007/s00262-002-0313-3
Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenviron-ment. Curr Opin Immunol. 2013;25:268–76.
https://doi.org/10.1016/j.coi.2013.02.009 DOI: https://doi.org/10.1016/j.coi.2013.02.009
Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301–5.
https://doi.org/10.1126/science.1071059 DOI: https://doi.org/10.1126/science.1071059
Ochsenbein AF, Sierro S, Odermatt B, Pericin M, Karrer U, Hermans J, et al. Roles of tu-mour localization, second signals and cross priming in cytotoxic T-cell in-duction. Nature. 2001;411:1058–64.
https://doi.org/10.1038/35082583 DOI: https://doi.org/10.1038/35082583
Quereux G, Pandolfino MC, Knol AC, Khammari A, Volteau C, Nguyen JM, et al. Tissue prognostic markers for adoptive immunotherapy in melanoma. Eur J Derma-tol. 2007;17:295–301.
Gajewski TF. Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. Clin Cancer Res. 2007;13:5256–61.
https://doi.org/10.1158/1078-0432.ccr-07-0892 DOI: https://doi.org/10.1158/1078-0432.CCR-07-0892
Dréno B, Nguyen JM, Khammari A, Pandolfino MC, Tessier MH, Bercegeay S, et al. Random-ized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother. 2002;51:539–46.
https://doi.org/10.1007/s00262-002-0315-1 DOI: https://doi.org/10.1007/s00262-002-0315-1
Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, et al. In-doleamine 2,3-dioxygenase pathways of pathogenic inflammation and im-mune escape in cancer. Cancer Immunol Immunother. 2014;63:721–35.
https://doi.org/10.1007/s00262-014-1549-4 DOI: https://doi.org/10.1007/s00262-014-1549-4
Khammari A, Knol AC, Nguyen JM, Bossard C, Denis MG, Pandolfino MC, et al. Adoptive TIL transfer in the adjuvant setting for melanoma: long-term patient survival. J Immunol Res. 2014;2014:186212.
https://doi.org/10.1155/2014/186212 DOI: https://doi.org/10.1155/2014/186212
Pandolfino MC, Labarrière N, Tessier MH, Cassidanius A, Bercegeay S, Lemarre P, et al. High-scale expansion of melanoma-reactive TIL by a polyclonal stimulus: predictability and relation with disease advancement. Cancer Immunol Im-munother. 2001;50:134–40.
https://doi.org/10.1007/pl00006683 DOI: https://doi.org/10.1007/PL00006683
Chebassier N, El Houssein O, Viegas I, Dréno B. In vitro induction of matrix metallopro-teinase-2 and matrix metalloproteinase-9 expression in keratinocytes by bo-ron and manganese. Exp Dermatol. 2004;13:484–90.
https://doi.org/10.1111/j.0906-6705.2004.00197.x DOI: https://doi.org/10.1111/j.0906-6705.2004.00197.x
Paijens ST, Vledder A, De Bruyn M, Nijman HW. Tumor-infiltrating lymphocytes in the im-munotherapy era. Cell Mol Immunol. 2021;18:842–59.
https://doi.org/10.1038/s41423-020-00565-9 DOI: https://doi.org/10.1038/s41423-020-00565-9
Ni J, Wang X, Stojanovic A, Zhang Q, Wincher M, Bühler L, et al. Single-cell RNA sequenc-ing of tumor-infiltrating NK cells reveals that inhibition of transcription fac-tor HIF-1α unleashes NK cell activity. Immunity. 2020;52:1075–87.e8.
https://doi.org/10.1016/j.immuni.2020.05.001 DOI: https://doi.org/10.1016/j.immuni.2020.05.001
Mao L, Qi Z, Zhang L, Guo J, Si L. Immunotherapy in acral and mucosal melanoma: current status and future directions. Front Immunol. 2021;12:680407.
https://doi.org/10.3389/fimmu.2021.680407 DOI: https://doi.org/10.3389/fimmu.2021.680407
LOrphelin JM, Le Naour S, Dalle S, Varey E, Dupuy A, Montaudie H, et al. Epidemiology and characteristics of acral lentiginous melanoma compared to lentigo mela-noma in France: a multicentric retrospective study from the French cohort RIC-Mel database. Eur J Dermatol. 2022;32:691–7.
https://doi.org/10.1684/ejd.2022.4357 DOI: https://doi.org/10.1684/ejd.2022.4357
Dudley ME, Wunderlich JR, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastat-ic melanoma. J Immunother. 2002;25:243–51.
https://doi.org/10.1097/00002371-200205000-00007 DOI: https://doi.org/10.1097/00002371-200205000-00007
Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, et al. Lifileucel, a tu-mor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39:2656–66.
https://doi.org/10.1200/jco.21.00612 DOI: https://doi.org/10.1200/JCO.21.00612
Shi LZ, Goswami S, Fu T, Guan B, Chen J, Xiong L, et al. Blockade of CTLA-4 and PD-1 en-hances adoptive T-cell therapy efficacy in an ICOS-mediated manner. Cancer Immunol Res. 2019;7:1803–12.
https://doi.org/10.1158/2326-6066.cir-18-0873 DOI: https://doi.org/10.1158/2326-6066.CIR-18-0873
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2023 Jean-Matthieu L'Orphelin, Ugo Lancien , Jean-Michel Nguyen , Francisco J.S. Coronilla, Soraya Saiagh , Julie Cassecuel , Lise Boussemart, Anne Dompmartin , Brigitte Dréno
This work is licensed under a Creative Commons Attribution 4.0 International License.
