Top

Published in:

01-08-2020 | Melanoma | Clinical Trial Report

Tumor infiltrating 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

Authors: Amir Khammari, Jean-Michel Nguyen, Marie-Thérèse Leccia, Bernard Guillot, Soraya Saiagh, Marie-Christine Pandolfino, Anne-Chantal Knol, Gaëlle Quéreux, Anne Chiffolettau, Nathalie Labarrière, Brigitte Dréno

Published in: Cancer Immunology, Immunotherapy | Issue 8/2020

Abstract

Background

Adoptive tumor-infiltrating lymphocytes (TIL) therapy and interleukin-2 (IL-2) have been investigated in melanoma.

Aim

To confirm previously observed preventive effects of TIL + IL2 in a subgroup of patients with relapsing metastatic stage III melanoma.

Methodology

Open-label, randomized two-group, multicenter five-year trial in adult stage III melanoma patients with only one invaded lymph node after complete resection. Patients received TIL + IL2 or abstention. TIL + IL2 was administered within 8 weeks after lymph node resection and 4 weeks after. Disease-free survival was assessed every 2 months up to month 18, every 3 months up to month 36 and every 4 months up to 5 years. A once-a-year follow-up was scheduled beyond the five-year follow-up. Safety was assessed throughout the trial.

Results

Overall, 49 patients accounted for the modified intent-to-treat and 47 for the PP. Slightly more male than female patients participated; mean age was 57.7 ± 11.4 years in the TIL + IL2 group and 53.5 ± 13.0 years in the abstention group. After 5 years of follow-up, 11/26 patients in the TIL + IL2 group and 13/23 in the abstention group had relapsed. There was no statistical difference between the groups (HR: 0.63 CI 95% [0.28–1.41], p = 0.258), nine patients in the TIL + IL2 and 11 in the abstention group died with no significant difference between the two groups (HR: 0.65 CI95% [0.27 − 1.59], p = 0.34). Safety was good.

Conclusion

We did not confirm results of a previous trial. However, ulceration of the primary melanoma may be considered predictive of the efficacy of TIL in melanoma in adjuvant setting, in a manner similar to interferon α.

Available only for authorised users

Luke JJ, Flaherty KT, Ribas A, Long GV (2017) Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol 14(8):463–482PubMed

Svedman FC, Pillas D, Taylor A, Kaur M, Linder R, Hansson J (2016) Stage-specific survival and recurrence in patients with cutaneous malignant melanoma in Europe—a systematic review of the literature. Clin Epidemiol 8:109–122PubMedPubMedCentral

Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL et al (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377(14):1345–1356PubMedPubMedCentral

Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE et al (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313(23):1485–1492PubMed

Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS et al (1994) Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst 86(15):1159–1166PubMed

Dudley ME, Wunderlich JR, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL et al (2002) A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother 25(3):243–251PubMedPubMedCentral

Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ et al (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594):850–854PubMedPubMedCentral

Dudley ME, Gross CA, Langhan MM, Garcia MR, Sherry RM, Yang JC et al (2010) CD8+ enriched "young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res 16(24):6122–6131PubMedPubMedCentral

Wu R, Forget MA, Chacon J, Bernatchez C, Haymaker C, Chen JQ et al (2012) Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. Cancer J 18(2):160–175PubMedPubMedCentral

10.

Andersen R, Donia M, Ellebaek E, Borch TH, Kongsted P, Iversen TZ et al (2016) long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL2 regimen. Clin Cancer Res 22(15):3734–3745PubMed

11.

Dreno B, Nguyen JM, Khammari A, Pandolfino MC, Tessier MH, Bercegeay S et al (2002) Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother 51(10):539–546PubMed

12.

Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R et al (2014) Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother 63(7):721–735PubMedPubMedCentral

13.

Khammari A, Nguyen JM, Pandolfino MC, Quereux G, Brocard A, Bercegeay S et al (2007) 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 56(11):1853–1860PubMed

14.

Khammari A, Knol AC, Nguyen JM, Bossard C, Denis MG, Pandolfino MC et al (2014) Adoptive TIL transfer in the adjuvant setting for melanoma: long-term patient survival. J Immunol Res 2014:186212PubMedPubMedCentral

15.

Lotze MT, Frana LW, Sharrow SO, Robb RJ, Rosenberg SA (1985) In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2. J Immunol 134(1):157–66PubMed

16.

Lotze MT, Matory YL, Ettinghausen SE, Rayner AA, Sharrow SO, Seipp CA et al (1985) In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J Immunol 135(4):2865–75PubMed

17.

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655PubMed

18.

Karnofsky D, Burchenal J (1949) Evaluation of chemotherapeutic agents in cancer. MacLoad, editor. Columbia University Press, New York

19.

Keung EZ, Gershenwald JE (2018) The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care. Expert Rev Anticancer Ther 18(8):775–784PubMed

20.

Jotereau F, Pandolfino MC, Boudart D, Diez E, Dreno B, Douillard JY et al (1991) High-fold expansion of human cytotoxic T-lymphocytes specific for autologous melanoma cells for use in immunotherapy. J Immunother 10(6):405–411PubMed

21.

Pandolfino MC, Labarriere N, Tessier MH, Cassidanius A, Bercegeay S, Lemarre P et al (2001) High-scale expansion of melanoma-reactive TIL by a polyclonal stimulus: predictability and relation with disease advancement. Cancer Immunol Immunother 50(3):134–140PubMed

22.

Tessier MH, Pandolfino MC, Jotereau F, Boudart D, Litoux P, Dreno B (1996) Home therapy with autologous tumor-infiltrating lymphocytes and subcutaneous interleukin-2 in metastatic melanoma. Eur J Cancer Engl 32a:735–736

23.

Gervois N, Heuze F, Diez E, Jotereau F (1990) Selective expansion of a specific anti-tumor CD8+ cytotoxic T lymphocyte clone in the bulk culture of tumor-infiltrating lymphocytes from a melanoma patient: cytotoxic activity and T cell receptor gene rearrangements. Eur J Immunol 20(4):825–831PubMed

24.

Pandolfino MC, Saiagh S, Knol AC, Dreno B (2010) Comparison of three culture media for the establishment of melanoma cell lines. Cytotechnology 62(5):403–412PubMedPubMedCentral

25.

Chebassier N, El Houssein O, Viegas I, Dreno B (2004) In vitro induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression in keratinocytes by boron and manganese. Exp Dermatol 13(8):484–490PubMed

26.

Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E et al (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci U.S.A 99(25):16168–16173PubMedPubMedCentral

27.

Labarriere N, Pandolfino MC, Gervois N, Khammari A, Tessier MH, Dreno B et al (2002) Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients. Cancer Immunol Immunother 51(10):532–538PubMed

28.

Benlalam H, Vignard V, Khammari A, Bonnin A, Godet Y, Pandolfino MC et al (2007) Infusion of Melan-A/Mart-1 specific tumor-infiltrating lymphocytes enhanced relapse-free survival of melanoma patients. Cancer Immunol Immunother 56(4):515–526PubMed

29.

Vignard V, Lemercier B, Lim A, Pandolfino MC, Guilloux Y, Khammari A et al (2005) Adoptive transfer of tumor-reactive Melan-A-specific CTL clones in melanoma patients is followed by increased frequencies of additional Melan-A-specific T cells. J Immunol 175(7):4797–4805PubMed

30.

Zippel D, Friedman-Eldar O, Rayman S, Hazzan D, Nissan A, Schtrechman G et al (2019) Tissue harvesting for adoptive tumor infiltrating lymphocyte therapy in metastatic melanoma. Anticancer Res 39(9):4995–5001PubMed

31.

Eggermont AMM, Robert C, Suciu S (2018) Adjuvant pembrolizumab in resected stage III melanoma. N Engl J Med U S 379:593–595

32.

Jewell R, Elliott F, Laye J, Nsengimana J, Davies J, Walker C et al (2015) The clinicopathological and gene expression patterns associated with ulceration of primary melanoma. Pigment Cell Melanoma Res 28(1):94–104PubMed

33.

Rohaan MW, van den Berg JH, Kvistborg P, Haanen JBAG (2018) Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option. J Immunother Cancer 6(1):102PubMedPubMedCentral

34.

Zhang X, Zhao Y, Ye Y, Li S, Qi S, Yang Y et al (2015) Lesional infiltration of mast cells, Langerhans cells, T cells and local cytokine profiles in alopecia areata. Arch Dermatol Res 307(4):319–331PubMed

35.

Gonzalez R, Torres-Lopez E (2014) Immunological basis of melanoma-associated vitiligo-like depigmentation. Actas Dermosifiliogr 105(2):122–127PubMed

36.

Boniface K, Seneschal J, Picardo M, Taieb A (2018) Vitiligo: focus on clinical aspects, immunopathogenesis, and therapy. Clin Rev Allergy Immunol 54(1):52–67PubMed

Title: Tumor infiltrating 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
Authors: Amir Khammari
Jean-Michel Nguyen
Marie-Thérèse Leccia
Bernard Guillot
Soraya Saiagh
Marie-Christine Pandolfino
Anne-Chantal Knol
Gaëlle Quéreux
Anne Chiffolettau
Nathalie Labarrière
Brigitte Dréno
Publication date: 01-08-2020
Publisher: Springer Berlin Heidelberg
Keywords: Melanoma
Melanoma
Published in: Cancer Immunology, Immunotherapy / Issue 8/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02572-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Aim

Methodology

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 8/2020

Interleukin-33 pretreatment promotes metastatic growth of murine melanoma by reducing the cytotoxic capacity of CD8+ T cells and enhancing regulatory T cells

A phase I study of multi-HLA-binding peptides derived from heat shock protein 70/glypican-3 and a novel combination adjuvant of hLAG-3Ig and Poly-ICLC for patients with metastatic gastrointestinal cancers: YNP01 trial

Outcomes with immune checkpoint inhibitors for relapsed small-cell lung cancer in a Swiss cohort

Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment

Tumor-infiltrating CD39+CD8+ T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients

Characterization of CD103+ CD8+ tissue-resident T cells in esophageal squamous cell carcinoma: may be tumor reactive and resurrected by anti-PD-1 blockade

Keynote webinar | Spotlight on antibody–drug conjugates in cancer