Journal Article

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

Garrett-Mayer, Elizabeth, Evavold, Brian D, Godellas, Constantine, Scurti, Gina M, Kolawole, Elizabeth Motunrayo, Moore, Tamson, Courtney Regan Wagner, Clark, Joseph I, Ann Lau Clark, Orentas, Rimas, Hellman, Lance M, Huyke, Fernando A, Nishimura, Michael I, Shirai, Keisuke, Baker, Brian M, Eby, Jonathan M, Embree, Heather D, Le Poole, I Caroline, Dellacecca, Emilia, Singh, Nishant K, Hutchens, Kelli A, Siao-Yi Wang, Li, Mingli, Calabrese, Kelly M, Dropulic, Boro, Stiff, Patrick J

2018

Overview

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.

• Publisher: Springer Nature B.V
• Subject: Adoptive transfer / Biological activity / CCR7 protein / CD25 antigen / CD34 antigen / CD4 antigen / CD69 antigen / CD8 antigen / Cell activation / Cell therapy / Chemotherapy / Clinical trials / CTLA-4 protein / Interleukin 15 / Interleukin 2 / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Melanoma / Memory cells / Metastases / Metastasis / Patients / PD-1 protein / Remission / Skin cancer / T cell receptors / Tumor necrosis factor / Vitiligo