Abstract

Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients1,2. In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy3. Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy4. To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg−1 and nivolumab 1 mg kg−1, as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity.

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Data availability

The RNA and DNA sequencing datasets generated during the current study have been deposited into the European Genome-phenome Archive under accession number EGAS00001003099 and are available on request. Every request will be reviewed by the institutional review board of the NKI; the researcher will need to sign a data access agreement with the NKI after approval. The TCR sequencing data that support the findings of this study are available from Adaptive Biotechnologies; however, restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. However, data are available from the authors on reasonable request and with the permission of Adaptive Biotechnologies. The DSP data that support the findings of this study are available from NanoString; however, restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. However, data are available from the authors on reasonable request and with permission from NanoString.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

We thank the patients and their families for participating in the study. We thank A. Gangaev for performing the experiments involving MHC tetramer staining; M. Valenti, T. Kuilman, and other members from the Blank, Peeper, and Schumacher laboratory for valuable discussions; W. Uyterlinde, A. Koenen, M. Wouters, and J. vd Hage for the clinical care of the patients included in the trial; C. Bierman for assisting with the pathological revisions of tumor samples; the NKI-AVL flow facility and the NKI-AVL Core Facility Molecular Pathology & Biobanking for supplying the NKI-AVL biobank material and/or laboratory support; E. Hooijberg for supervising the immunohistochemistry analysis; S. Vanhoutfin for financial management; A. Cesano for scientific input on the NanoString analyses; and D. Walker, C. Pfeiffer, B. Lamon, B. Stegenga, and V. Goodman from Bristol-Myers Squibb for scientific input and support.

Author information

Affiliations

  1. Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands

    • Christian U. Blank
    • , Elisa A. Rozeman
    • , Johannes V. van Thienen
    • , Henk A. Mallo
    • , Sandra Adriaansz
    •  & John B. A. G. Haanen
  2. Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    • Christian U. Blank
    • , Elisa A. Rozeman
    • , Lorenzo F. Fanchi
    • , Pia Kvistborg
    • , Oscar Krijgsman
    • , Marlous van den Braber
    • , Daisy Philips
    • , Daniel S. Peeper
    • , John B. A. G. Haanen
    •  & Ton N. Schumacher
  3. Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands

    • Karolina Sikorska
    • , Loes M. Pronk
    • , Lindsay G. Grijpink-Ongering
    •  & Harm van Tinteren
  4. Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    • Bart van de Wiel
    •  & Annegien Broeks
  5. Surgical Oncology Department, Netherlands Cancer Institute, Amsterdam, The Netherlands

    • Sylvia ter Meulen
    •  & Alexander C. J. van Akkooi
  6. Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    • Annemarie Bruining
  7. Adaptive Biotechnologies, Seattle, WA, USA

    • Rachel M. Gittelman
  8. NanoString Technologies, Inc., Seattle, WA, USA

    • Sarah Warren

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Contributions

C.U.B. and T.N.S. designed the study and wrote the manuscript. E.A.R. analyzed and interpreted the clinical and translational data. L.F.F. performed the bioinformatics analyses. K.S. performed the statistical analysis on the clinical data. B.vd.W. assessed the pathological response of neoadjuvant-treated patients. M.vd.B. and D.P. performed the experiments for the MHC tetramer analysis. P.K. supervised the MHC tetramer analysis. C.U.B., J.V.v.T, J.B.A.G.H., H.A.M., S.A., and S.t.M., were responsible for the clinical care of the patients. L.G.G.-O. was responsible for data management. L.M.P. is the clinical project manager for this study. A. Broeks was responsible for storing and processing the tumor samples. A. Bruining performed the radiological evaluations. S.W. was responsible for the DSP analysis. R.M.G. was responsible for TCR sequencing. H.v.T. created the statistical design. A.C.J.v.A. performed the surgeries. A.C.J.v.A., D.S.P., O.K., and J.B.A.G.H. gave critical input. All authors critically revised the manuscript.

Competing interests

C.U.B. reports personal fees for advisory roles for MSD, BMS, Roche, GSK, Novartis, Pfizer, GenMab, and Lilly, and grants from BMS, NanoString, and Novartis,outside the submitted work. E.A.R. reports travel support from NanoString Technologies and MSD, outside the submitted work. L.F.F., K.S., B.vd.W., P.K., O.K., M.vd.B., D.P., A. Broeks., H.A.M., S.A., S.t.M., L.M.P., L.G.G.-O., A. Bruining, and H.v.T. have nothing to disclose. J.V.v.T reports travel support from Roche, outside the submitted work. R.M.G. has a financial interest in Adaptive Biotechnologies. S.W. is an employee of and is a stockholder in NanoString Technologies, has an advisory role with Roche, and is a former employee of the Oncofactor Corporation, outside the submitted work. D.S.P. reports research support from BMS. J.B.A.G.H. reports that NKI received fees for his advisory roles from BMS, MSD, Roche, Neon Therapeutics, Immunocore, Novartis, AstraZeneca/MedImmune, Pfizer, and Ipsen; NKI received grants from BMS, Merck, Novartis, and Neon Therapeutics, outside the submitted work. A.C.J.v.A. reports personal fees for an advisory role with Amgen, Bristol-Myers Squibb, Novartis, MSD-Merck, and Merck-Pfizer, and grants from Amgen and Novartis, all outside the submitted work. T.N.S. is consultant for Adaptive Biotechnologies, AIMM Therapeutics, Amgen, Neon Therapeutics, Scenic Biotech, and reports grant/research support from Merck, Bristol-Myers Squibb, and Merck KGaA; he is a stockholder in AIMM Therapeutics and Neon Therapeutics.

Corresponding authors

Correspondence to Christian U. Blank or Ton N. Schumacher.

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DOI

https://doi.org/10.1038/s41591-018-0198-0