Phase I/II study protocol to assess safety and efficacy of adoptive cell therapy with anti-PD-1 plus low-dose pegylated-interferon-alpha in patients with metastatic melanoma refractory to standard of care treatments: the ACTME trial

Monique K van der Kooij, Els M E Verdegaal, Marten Visser, Linda de Bruin, Caroline E van der Minne, Pauline M Meij, Inge C F M Roozen, Mare A Jonker, Shelley van den Bosch, Gerrit-Jan Liefers, Frank M Speetjens, Sjoerd H van der Burg, Ellen Kapiteijn, Monique K van der Kooij, Els M E Verdegaal, Marten Visser, Linda de Bruin, Caroline E van der Minne, Pauline M Meij, Inge C F M Roozen, Mare A Jonker, Shelley van den Bosch, Gerrit-Jan Liefers, Frank M Speetjens, Sjoerd H van der Burg, Ellen Kapiteijn

Abstract

Introduction: Treatment with anti-PD-1 immunotherapy does not lead to long-lasting clinical responses in approximately 60% of patients with metastatic melanoma. These refractory patients, however, can still respond to treatment with tumour infiltrating lymphocytes (TIL) and interferon-alpha (IFNa). A combination of TIL, pegylated-interferon-alpha (PEG-IFNa) and anti-PD-1 is expected to provide a safe, feasible and effective therapy for patients with metastatic melanoma, who are refractory to standard of care treatment options.

Methods and analysis: Patients are treated in two phases. In phase I, the safety of the combination TIL and anti-PD-1 is assessed (cohort 1) according to CTCAE 4.03 criteria. Subsequently, the safety of cotreatment with PEG-IFNa is tested in cohort 2. The efficacy will be evaluated in the second phase of the trial. Efficacy is evaluated according to RECIST 1.1 and immune-related response criteria. Clinical and immunological parameters will be evaluated for their relation with clinical responsiveness.

Ethics and dissemination: Ethical approval of the trial was obtained from the Central Committee on Research Involving Human Subjects in the Netherlands. The trial results will be shared with the scientific community at (inter)national conferences and by publication in a peer-reviewed journal.

Trial registration number: NCT03638375; Pre-results.

Keywords: dermatological tumours; immunology; oncology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Resolving four of the most important aspects curtailing the efficacy and feasibility of current immunotherapies: (1) providing tumour-reactive TIL; (2) alleviating immune checkpoint inhibition; (3) reducing toxicity of ACT treatment; (4) Minimalising hospitalisation and patient burden. ACT, adoptive cell therapy; IFNa, interferon-alpha; TIL, tumour infiltrating lymphocytes.
Figure 2
Figure 2
Study design of ACTME trial. Blood and serum are collected at indicated time-points (red blood drop). In cohort 1, treatment with PEG-IFNa is omitted. In cohort 2 and phase II, pegylated-IFNa is added to the treatment with aPD1 and TIL. aPD1, anti-PD-1; IFNa, interferon-alpha; PEG-IFNa, pegylated-interferon-alpha; TIL, tumour infiltrating lymphocytes.
Figure 3
Figure 3
Number of patients treated per cohort and in the two study phases and data safety monitoring during ACTME trial. aPD1, anti-PD-1 treatment; DSMB; Data Safety Monitoring Board; IFNa, peginterferon-alpha2a; TIL, tumour infiltrating lymphocytes; trSAE, treatment-related serious adverse event.

References

    1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. . Five-Year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381:1535–46. 10.1056/NEJMoa1910836
    1. Tumeh PC, Harview CL, Yearley JH, et al. . PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568–71. 10.1038/nature13954
    1. Dudley ME, Wunderlich JR, Yang JC, et al. . Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346–57. 10.1200/JCO.2005.00.240
    1. Dudley ME, Yang JC, Sherry R, et al. . Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 2008;26:5233–9. 10.1200/JCO.2008.16.5449
    1. Rosenberg SA, Yang JC, Sherry RM, et al. . Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011;17:4550–7. 10.1158/1078-0432.CCR-11-0116
    1. Rosenberg SA, Packard BS, Aebersold PM, et al. . Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 1988;319:1676–80. 10.1056/NEJM198812223192527
    1. Verdegaal E, van der Kooij MK, Visser M, et al. . Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I/II study. J Immunother Cancer 2020;8:e000166. 10.1136/jitc-2019-000166
    1. Verdegaal EME, Visser M, Ramwadhdoebé TH, et al. . Successful treatment of metastatic melanoma by adoptive transfer of blood-derived polyclonal tumor-specific CD4+ and CD8+ T cells in combination with low-dose interferon-alpha. Cancer Immunol Immunother 2011;60:953–63. 10.1007/s00262-011-1004-8
    1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252–64. 10.1038/nrc3239
    1. Rosenberg SA, Restifo NP, Yang JC, et al. . Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008;8:299–308. 10.1038/nrc2355
    1. Sim GC, Chacon J, Haymaker C, et al. . Tumor-infiltrating lymphocyte therapy for melanoma: rationale and issues for further clinical development. BioDrugs 2014;28:421–37. 10.1007/s40259-014-0097-y
    1. Rohaan MW, van den Berg JH, Kvistborg P, et al. . Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option. J Immunother Cancer 2018;6:102. 10.1186/s40425-018-0391-1
    1. Yang JC. Toxicities associated with adoptive T-cell transfer for cancer. Cancer J 2015;21:506–9. 10.1097/PPO.0000000000000157
    1. Innamarato P, Kodumudi K, Asby S, et al. . Reactive myelopoiesis triggered by Lymphodepleting chemotherapy limits the efficacy of adoptive T cell therapy. Mol Ther 2020;28:2252–70. 10.1016/j.ymthe.2020.06.025
    1. Sarnaik A, Khushalani NI, Chesney JA, et al. . Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies. J Clin Oncol 2020;38(15_suppl):10006.
    1. Gattinoni L, Klebanoff CA, Palmer DC, et al. . Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 2005;115:1616–26. 10.1172/JCI24480
    1. Besser MJ, Shapira-Frommer R, Treves AJ, et al. . Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 2010;16:2646–55. 10.1158/1078-0432.CCR-10-0041
    1. Fried MW, Shiffman ML, Reddy KR, et al. . Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82. 10.1056/NEJMoa020047
    1. Kartal ED, Alpat SN, Ozgunes I, et al. . Adverse effects of high-dose interferon-alpha-2a treatment for chronic hepatitis B. Adv Ther 2007;24:963–71. 10.1007/BF02877700
    1. Posthuma EFM, Marijt EWAF, Barge RMY, et al. . Alpha-interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease. Biol Blood Marrow Transplant 2004;10:204–12. 10.1016/j.bbmt.2003.11.003
    1. Wolchok JD, Hoos A, O'Day S, et al. . Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412–20. 10.1158/1078-0432.CCR-09-1624
    1. Schwartz LH, Litière S, de Vries E, et al. . RECIST 1.1-Update and clarification: from the RECIST Committee. Eur J Cancer 2016;62:132–7. 10.1016/j.ejca.2016.03.081
    1. Krieg C, Nowicka M, Guglietta S, et al. . High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med 2018;24:144–53. 10.1038/nm.4466
    1. Santegoets SJAM, Dijkgraaf EM, Battaglia A, et al. . Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry. Cancer Immunol Immunother 2015;64:1271–86. 10.1007/s00262-015-1729-x
    1. Welters MJ, van der Sluis TC, van Meir H, et al. . Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Sci Transl Med 2016;8:334ra52. 10.1126/scitranslmed.aad8307
    1. Betts MR, Brenchley JM, Price DA, et al. . Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 2003;281:65–78. 10.1016/S0022-1759(03)00265-5
    1. Melief SM, Visconti VV, Visser M, et al. . Long-Term survival and clinical benefit from adoptive T-cell transfer in stage IV melanoma patients is determined by a Four-parameter tumor immune signature. Cancer Immunol Res 2017;5:170–9. 10.1158/2326-6066.CIR-16-0288
    1. A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med 2001;20:859–66. 10.1002/sim.721
    1. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982;38:143–51. 10.2307/2530297
    1. Beyrend G, Stam K, Höllt T, et al. . Cytofast: A workflow for visual and quantitative analysis of flow and mass cytometry data to discover immune signatures and correlations. Comput Struct Biotechnol J 2018;16:435–42. 10.1016/j.csbj.2018.10.004

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