Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells

Abstract

Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4+ and CD8+ T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4+ and CD8+ T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t+ cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255 days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma patients had clinical and/or biological activity without serious adverse events.

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Change history

  • 20 December 2017

    The authors would like to make the following corrections to the published article.

Abbreviations

2D:

Two-dimensional

3D:

Three-dimensional

CCR7:

C–C motif chemokine receptor 7

CD34t:

Truncated CD34

FDA:

U.S. Food and Drug Administration

pMHC:

Peptide-loaded MHC complexes, in this study, tyrosinase peptide-loaded HLA-A2 MHC molecules

rhIL-2:

Recombinant human IL-2

rhIL-15:

Recombinant human IL-15

TIM-3:

T cell immunoglobulin and mucin-domain containing-3

Treg :

Regulatory CD4+ T cells

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Acknowledgements

All flow cytometry was performed in the Loyola University, Chicago, Flow Cytometry Core, with the assistance of Patricia Simms.

Funding

This study was funded by National Institute of Health Grants: R43 CA126461 (Boro Dropulic), R44 CA126461 (Boro Dropulic), R01 CA90873 (Michael I. Nishimura), R01 CA104947 (Michael I. Nishimura), R01 CA104947-S1 (Michael I. Nishimura), P01 CA154778 (Michael I. Nishimura), R01 AI129543-01 (Brian M. Baker, Brian D. Evavold, Michael I. Nishimura), R01 AI096879 (Brian D. Evavold).

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Correspondence to Tamson Moore.

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Conflict of interest

Author Joseph I. Clark received speaking honorariums from Merck and Bristol-Myers Squibb, and is an unpaid member of the steering committee for the Prometheus PROCLAIM high-dose IL-2 database. Other authors report no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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A correction to this article is available online at https://doi.org/10.1007/s00262-017-2102-z.

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Moore, T., Wagner, C.R., Scurti, G.M. et al. Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells. Cancer Immunol Immunother 67, 311–325 (2018). https://doi.org/10.1007/s00262-017-2073-0

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Keywords

  • Adoptive transfer
  • Metastatic melanoma
  • Clinical trial
  • Transduced T cells
  • Immunotherapy
  • Vitiligo