In addition to T-cell receptor signals, T lymphocytes require costimulatory signals for robust activation. Among these, those mediated by 4-1BB (CD137, TNFRSF9) are critical for tumor immunity. 4-1BB is expressed in T-cell receptor–activated lymphocytes as well as natural killer cells and other hematopoietic and nonhematopoietic cells. 4-1BB ligation induces a signaling cascade that results in cytokine production, expression of antiapoptotic molecules, and enhanced immune responses. In line with the described function of 4-1BB, its addition to CD3ζ chimeric antigen receptors (CARs) increases their capacity to provoke T-cell expansion and antitumor activity. The results of preclinical studies with 4-1BB CARs have been corroborated by encouraging results from clinical trials. Advantages and disadvantages of 4-1BB CARs versus CARs bearing other costimulatory components remain to be fully elucidated. In this review, we discuss the properties of 4-1BB, the design of 4-1BB CARs, and the function of T lymphocytes and natural killer cells expressing them.
From the Departments of *Pediatrics and †Physiology, National University of Singapore, Singapore; and ‡Department of Pediatrics, Niigata University, Niigata, Japan.
A Singapore Translational Research Investigator Award from the National Medical Research Council of Singapore and the Viva Foundation for Children with Cancer supported this work.
D.C. and C.I. are the inventors of an anti-CD19-BB-ζ receptor licensed to Juno Therapeutics. D.C. is the inventor on a filed patent for the CD16V-BB-ζ receptor. The remaining author has disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Reprints: Dario Campana, MD, PhD, Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore Centre for Translational Medicine, 14 Medical Dr, Level 9, South Singapore 117599. E-mail: firstname.lastname@example.org.