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Tumor Immune Profiling-Based Neoadjuvant Immunotherapy for Locally Advanced Melanoma

  • Melanoma
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The frequency of “exhausted” or checkpoint-positive (PD-1+CTLA-4+) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade.

Methods

Pretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan–Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.

Results

Of the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis.

Conclusion

The results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.

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References

  1. Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008;105:3005–10.

    Article  CAS  Google Scholar 

  2. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    Article  CAS  Google Scholar 

  3. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  CAS  Google Scholar 

  4. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44.

    Article  CAS  Google Scholar 

  5. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–17.

    Article  CAS  Google Scholar 

  6. Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:1600–9.

    Article  CAS  Google Scholar 

  7. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–35.

    Article  CAS  Google Scholar 

  8. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789–801.

    Article  CAS  Google Scholar 

  9. Amaria RN, Menzies AM, Burton EM, et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. Lancet Oncol. 2019;20:e378–89.

    Article  Google Scholar 

  10. Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018;24:1649–54.

    Article  CAS  Google Scholar 

  11. Rozeman EA, Menzies AM, van Akkooi ACJ, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019;20:948–60.

    Article  CAS  Google Scholar 

  12. Carlino MS, Long GV, Schadendorf D, et al. Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: a randomised clinical trial. Eur J Cancer. 2018;101:236–43.

    Article  CAS  Google Scholar 

  13. Daud AI, Wolchok JD, Robert C, et al. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin Oncol. 2016;34:4102–9.

    Article  CAS  Google Scholar 

  14. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.

    Article  Google Scholar 

  15. McGranahan N, Furness AJS, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–9.

    Article  CAS  Google Scholar 

  16. Huang AC, Postow MA, Orlowski RJ, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545:60–5.

    Article  CAS  Google Scholar 

  17. Daud AI, Loo K, Pauli ML, et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J Clin Investig. 2016;126:3447–52.

    Article  Google Scholar 

  18. Loo K, Tsai KK, Mahuron K, et al. Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy. JCI Insight. 2017;2(14):e93433. https://doi.org/10.1172/jci.insight.93433.

    Article  PubMed Central  Google Scholar 

  19. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.

    Article  CAS  Google Scholar 

  20. Pauken KE, Sammons MA, Odorizzi PM, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016;354:1160–5.

    Article  CAS  Google Scholar 

  21. Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med. 2019;25:454–61.

    Article  CAS  Google Scholar 

  22. Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24:1655–61.

    Article  CAS  Google Scholar 

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Acknowledgment

We gratefully acknowledge the patients who participated in this study. This work was supported by grants to Michael D. Rosenblum (NIH DP2-AR068130, K08-AR062064, AR066821 Burroughs Wellcome CAMS-1010934), Adil I. Daud (Amoroso and Cook fund, Parker Institute for Cancer Immunotherapy), and Lauren S. Levine (Conquer Cancer Foundation Young Investigator Award CA-0122026). Kelly M. Mahuron was supported by the NIH T32 training grant in Gastrointestinal Surgery T32DK007573.

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Correspondence to Adil I. Daud MBBS.

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Disclosures

Alain P. Algazi discloses institutional research funding from Novartis, Merck, BMS OncoSec, Acerta, AstraZeneca, MedImmune, Tessa, Celldex, and Celgene; consulting with stock options for Oncosec and Valitor; paid advisory board positions for Array and Regeneron; and an unpaid advisory role with Sensei Biotherapeutics. Adil I. Daud discloses research funding from the Amoroso and Cook fund, Parker Institute for Cancer Immunotherapy, Novartis, Merck, BMS, Incyte, AbbVie, OncoSec, Xencor, Pfizer, Roche/Genentech, and Exelixis; Advisory Board participation from Amgen, Array, and Roche/Genentech; and stock ownership in Trex Bio and Pionyr Immunotherapeutics. Matthew F. Krummel is the founder and board member of Pionyr Immunotherapeutics. Lauren S. Levine has received research funding from the Conquer Cancer Foundation CA-0122026. Kelly M. Mahuron received support by the NIH T32 training grant in Gastrointestinal Surgery T32DK007573. Michael D. Rosenblum is a consultant with equity ownership for Trex Bio, holds equity in Sitryx Bio, and has received funding on grants NIH DP2-AR068130, K08-AR062064, AR066821 Burroughs Wellcome CAMS-1010934. Matthew H. Spitzer discloses research funding from Genentech/Roche, Pfizer, Valitor Inc., and Bristol-Myers Squibb, and is a paid consultant for Five Prime Therapeutics, Ono Pharmaceutical, and January, Inc. Katy K. Tsai discloses institutional research funding from BMS, Parker Institute for Cancer Immunotherapy, Oncosec, and Regeneron. The remaining authors have no conflicts of interest.

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Levine, L.S., Mahuron, K.M., Tsai, K.K. et al. Tumor Immune Profiling-Based Neoadjuvant Immunotherapy for Locally Advanced Melanoma. Ann Surg Oncol 27, 4122–4130 (2020). https://doi.org/10.1245/s10434-020-08648-7

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  • DOI: https://doi.org/10.1245/s10434-020-08648-7

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