Page 287 - Hematology_ Basic Principles and Practice ( PDFDrive )

238 Part III Immunologic Basis of Hematology

incorporation of an additional intracellular signaling domain derived
from costimulatory molecules, such as CD28 or 4-1BB, into second-
generation CARs augmented CAR-T-cell activation and antitumor
Antigen efficacy, and third-generation CARs include signaling domains from
recognition two costimulatory receptors. Currently, most CARs adhere to the
second-generation model. Which intracellular costimulatory domains
will work best in CARs and how many costimulatory domains are
required for optimal T-cell activation and antitumor efficacy are
under active investigation. Other outstanding questions in the bio-
Transmembrane chemistry of CARs concern the optimal number of functional ITAMs
domain present in ζ chain domains and the length and composition of the
transmembrane hinge domain and interdomain junctions. Defining
the biochemistry and signal transduction of CARs should permit
Co-stimulatory broadening its use to more common malignancies.
domain
The examples presented here are only a small subset of novel
approaches in use or being tested to modulate immune cell function
based upon our understanding of the molecular basis of T-cell activa-
CD3 chain tion. It is anticipated that as more is learned about the molecules and
pathways critical for control of T cell–mediated immunity, additional
new agents with greater efficacy and improved safety profiles will
Fig. 21.12 DESIGN OF A CHIMERIC ANTIGEN RECEPTOR T CELL. become available for clinical use. The advent of these new therapeutics
The modular design of successful chimeric antigen receptors (CARs) uses the and their potential to improve treatments for serious human diseases
knowledge gained through the study of fundamental properties of antigen underscore the importance of continued efforts to understand the
recognition and signaling pathways in immune cells. The extracellular antigen mechanisms of T-cell development and function.
recognition domain is typically derived from a single-chain variable fragment
of an antibody specific for an antigen expressed by the tumor cells. This
domain is coupled to a transmembrane domain, which has been derived from SUGGESTED READINGS
either CD8 or CD28 molecules. The CAR transmits an activation signal
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