Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2

Research output: Contribution to journalArticlepeer-review

Authors

  • Linh T Nguyen
  • Samuel D Saibil
  • Valentin Sotov
  • Michael X Le
  • Danny Ghazarian
  • Luisa Bonilla
  • Habeeb Majeed
  • David Hogg
  • Anthony M Joshua
  • Michael Crump
  • Norman Franke
  • Anna Spreafico
  • Aaron Hansen
  • Ayman Al-Habeeb
  • Wey Leong
  • Alexandra Easson
  • Michael Reedijk
  • David P Goldstein
  • David McCready
  • Kazuhiro Yasufuku
  • Thomas Waddell
  • Marcelo Cypel
  • Andrew Pierre
  • Bianzheng Zhang
  • Sarah Boross-Harmer
  • Jane Cipollone
  • Megan Nelles
  • Elizabeth Scheid
  • Michael Fyrsta
  • Charlotte S Lo
  • Jessica Nie
  • Jennifer Y Yam
  • Pei Hua Yen
  • Diana Gray
  • Vinicius Motta
  • Alisha R Elford
  • Stephanie DeLuca
  • Lisa Wang
  • Stephanie Effendi
  • Ragitha Ellenchery
  • Naoto Hirano
  • Pamela S Ohashi
  • Marcus O Butler

Colleges, School and Institutes

External organisations

  • Tumor Immunotherapy Program
  • Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • UNIVERSITY HEALTH NETWORK
  • Kinghorn Cancer Centre
  • Department of Otolaryngology
  • Department of Chemistry and Pharmacy
  • Drug Development Program
  • University of Toronto
  • 610 University Avenue
  • University College London Hospital
  • University of Oxford
  • UNIVERSITY COLLEGE LONDON

Abstract

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vβ chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).

Details

Original languageEnglish
Pages (from-to)773-785
Number of pages13
JournalCancer Immunology Immunotherapy
Volume68
Issue number5
Early online date11 Feb 2019
Publication statusPublished - 1 May 2019

Keywords

  • Adult, Cell Proliferation, Cells, Cultured, Female, Humans, Immunotherapy, Adoptive/methods, Interleukin-15/metabolism, Interleukin-2/therapeutic use, Lymphocytes, Tumor-Infiltrating/immunology, Male, Melanoma/immunology, Middle Aged, Neoplasm Metastasis, Skin Neoplasms/immunology, Treatment Outcome