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

• Type of Material: Article
• Authors: Tamson Moore, Loyola University Chicago; Courtney Regan Wagner, Loyola University Chicago; Gina M. Scurti, Loyola University Chicago; Kelli A. Hutchens, Loyola University Chicago; Constantine Godellas, Loyola University Chicago; Ann Lau Clark, Loyola University Chicago; Elizabeth Motunrayo Kolawole, Emory University; Lance M. Hellman, University of Notre Dame; Nishant K. Singh, University of Notre Dame; Fernando A. Huyke, University of Notre Dame; Siao-Yi Wang, Loyola University Chicago; Kelly M. Calabrese, Loyola University Chicago; Heather D. Embree, Lentigen Technol Inc; Rimas Orentas, Lentigen Technol Inc; Keisuke Shirai, Medical University of South Carolina; Emilia Dellacecca, Loyola University Chicago; Elizabeth Garrett-Mayer, Medical University of South Carolina; Mingli Li, Medical University of South Carolina; Jonathan M. Eby, Loyola University Chicago; Patrick J. Stiff, Loyola University Chicago; Brian Evavold, Emory University; Brian M. Baker, University of Notre Dame; I. Caroline Le Poole, Loyola University Chicago; Boro Dropulic, Lentigen Technol Inc; Joseph I. Clark, Loyola University Chicago; Michael I. Nishimura, Loyola University Chicago
• Language: English
• Date: 2018-02-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017, Springer-Verlag GmbH Germany.
• Final Published Version (URL): http://dx.doi.org/10.1007/s00262-017-2073-0
• Title of Journal or Parent Work: Cancer Immunology, Immunotherapy
• ISSN: 0340-7004
• Volume: 67
• Issue: 2
• Start Page: 311
• End Page: 325
• Grant/Funding Information: 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)
• Keywords: Clinical trial; Immunology; CANCER REGRESSION; Transduced T cells; PD-1 BLOCKADE; Vitiligo; Metastatic melanoma; Adoptive transfer; PHASE-I; EXPRESSION; Life Sciences & Biomedicine; Oncology; Science & Technology; Immunotherapy; ANTIGEN; IMMUNE CHECKPOINT BLOCKADE; IMMUNOTHERAPY; TUMOR-INFILTRATING LYMPHOCYTES; GENE-THERAPY; IN-VIVO
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology

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.