Selection of Shared and Neoantigen-Reactive T Cells for Adoptive Cell Therapy Based on CD137 Separation

• Published in: Frontiers in immunology Vol. 8; p. 1211
• Main Authors: Seliktar-Ofir, Sivan, Merhavi-Shoham, Efrat, Itzhaki, Orit, Yunger, Sharon, Markel, Gal, Schachter, Jacob, Besser, Michal J
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 10.10.2017
• Subjects: adoptive cell therapy; CD137; Immunology; melanoma; neoantigen; tumor antigen; tumor infiltrating lymphocytes (TIL); neoantigen; tumor antigen; melanoma; tumor infiltrating lymphocytes (TIL); CD137; adoptive cell therapy
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2017.01211

Adoptive cell therapy (ACT) of autologous tumor infiltrating lymphocytes (TIL) is an effective immunotherapy for patients with solid tumors, yielding objective response rates of around 40% in refractory patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TIL from the tumor tissue for expansion and infusion. Only a minor fraction of the administered T cells recognizes tumor antigens, such as shared and mutation-derived neoantigens, and consequently eliminates the tumor. Thus, there are many ongoing effects to identify and select tumor-specific TIL for therapy; however, those approaches are very costly and require months, which is unreasonable for most metastatic patients. CD137 (4-1BB) has been identified as a co-stimulatory marker, which is induced upon the specific interaction of T cells with their target cell. Therefore, CD137 can be a useful biomarker and an important tool for the selection of tumor-reactive T cells. Here, we developed and validated a simple and time efficient method for the selection of CD137-expressing T cells for therapy based on magnetic bead separation. CD137 selection was performed with clinical grade compliant reagents, and TIL were expanded in a large-scale manner to meet cell numbers required for the patient setting in a GMP facility. For the first time, the methodology was designed to comply with both clinical needs and limitations, and its feasibility was assessed. CD137-selected TIL demonstrated significantly increased antitumor reactivity and were enriched for T cells recognizing neoantigens as well as shared tumor antigens. CD137-based selection enabled the enrichment of tumor-reactive T cells without the necessity of knowing the epitope specificity or the antigen type. The direct implementation of the CD137 separation method to the cell production of TIL may provide a simple way to improve the clinical efficiency of TIL ACT.